SOS1 inhibitors

Abstract

The present invention relates to compounds that inhibit Son of Sevenless Homolog 1 (SOS1) activity. In particular, the present invention relates to compounds, pharmaceutical compositions, and methods of use, such as methods for treating cancer using the compounds and pharmaceutical compositions of the present invention.

Description

[Technical Field]

[0001] This invention relates to compounds that inhibit GTP-mediated nucleotide exchange of Son of Sevenless homolog 1 (SOS1). In particular, this invention relates to compounds, pharmaceutical compositions containing the compounds, and methods of use thereof. [Background technology]

[0002] The Ras family includes the v-Ki-ras2 Kirsten rat sarcoma virus oncogene homolog (KRAS), the neuroblastoma RAS virus oncogene homolog (NRAS), and the Harvey mouse sarcoma virus oncogene (HRAS), which critically regulate cell division, growth, and function in normal and altered states, including cancer (see, e.g., Simanshu et al., Cell, 2017.170(1):p.17-33, Matikas et al., Crit Rev Oncol Hematol, 2017.110:p.1-12). RAS proteins are activated by upstream signaling, including receptor tyrosine kinases (RTKs), and transmit signals to several downstream signaling pathways, such as the mitogen-activated protein kinase (MAPK) / extracellular signal-regulated kinase (ERK) pathway. Hyperactivation of RAS signaling is frequently observed in cancer as a result of mutations or alterations in RAS genes or other genes within the RAS pathway. Identifying strategies to inhibit RAS and RAS signaling is expected to be helpful in treating cancer and RAS-regulated conditions.

[0003] RAS proteins are guanosine triphosphates (GTPases) that cycle between an inactive guanosine diphosphate (GDP)-bound state and an active guanosine triphosphate (GTP)-bound state. Son of Sevenless homolog 1 (SOS1) is a guanine nucleotide exchange factor (GEF) that mediates the exchange from GDP to GTP, thereby activating the RAS protein. The RAS protein hydrolyzes GTP to GDP via intrinsic GTPase activity, which is greatly enhanced by GTPase-activating protein (GAP). This regulation via GAP and GEF is a mechanism by which activation and deactivation are tightly regulated under normal conditions. Mutations in several residues of all three RAS proteins are frequently observed in cancer, and these mutations cause RAS to maintain primarily the activated state (Sanchez-Vega et al., Cell, 2018.173:p.321-337; Li et al., Nature Reviews Cancer, 2018.18:p.767-777). Mutations at codons 12 and 13 are the most frequently mutated RAS residues, preventing GAP-stimulated GTP hydrolysis by blocking the interaction between the GAP protein and RAS. However, recent biochemical analyses have demonstrated that these mutant proteins still require nucleotide cycling for activation based on their endogenous GTPase activity and / or partial sensitivity to exogenous GTPases. Therefore, mutant RAS proteins are sensitive to inhibition of upstream factors such as SOS1 or SHP2, which are other upstream signaling molecules required for RAS activation (Hillig, 2019; Patricelli, 2016; Lito, 2016; Nichols, 2018).

[0004] The three major RAS-GEF families identified in mammalian cells are SOS, RAS-GRF, and RAS-GRP (Rojas, 2011). RAS-GRF and RAS-GRP are expressed in central nervous system cells and hematopoietic cells, respectively, while the SOS family is ubiquitous and is responsible for RTK signaling. The SOS family includes SOS1 and SOS2, and these proteins share approximately 70% sequence identity. SOS1 appears to be far more active than SOS2 because SOS2 degrades rapidly. SOS1 knockout is embryonically lethal, while mouse SOS2 knockout is viable. Using a tamoxifen-induced SOS1 knockout mouse model, we investigated the roles of SOS1 and SOS2 in adult mice and demonstrated that SOS1 knockout is viable, but SOS1 / 2 double knockout is not (Baltanas, 2013). This suggests functional redundancy and indicates that selective inhibition of SOS1 may have a sufficient therapeutic index for treating SOS1-RAS activation disorders.

[0005] The SOS protein is recruited to the phosphorylated RTK via interaction with growth factor receptor-binding protein 2 (GRB2). Recruitment to the plasma membrane brings SOS closer to the RAS, enabling SOS-mediated RAS activation. The SOS protein binds to the RAS via a binding site that promotes nucleotide exchange and an allosteric site that enhances SOS function by binding to GTP-binding RAS family proteins (Freedman et al., Proc. Natl. Acad. Sci, USA 2006. 103(45): p. 16692-97). Binding to the allosteric site is required for nucleotide exchange because it relieves steric occlusion of the RAS substrate binding site. The retention of the active conformation at the catalytic site after interaction with the allosteric site is maintained independently because the interaction of key domains in the activated state is enhanced. SOS1 mutations are found in Noonan syndrome, as well as in several cancers, including lung adenocarcinoma, embryonal rhabdomyosarcoma, Sertoli cell testicular tumor, and granuloma of the skin (see, for example, Denayer, E., et al, Genes Chromosomes Cancer, 2010. 49(3): p.242-52).

[0006] GTPase-activating proteins (GAPs) are proteins that stimulate the low intrinsic GTPase activity of RAS family members, thereby converting active GTP-binding RAS proteins into inactive GDP-binding RAS proteins (see, for example, Simanshu, DK, Cell, 2017, Ras Proteins and their Regulators in Human Disease). While activating changes in GEF SOS1 occur in cancer, inactivating mutations and loss-of-function changes in GAP neurofibromin 1 (NF-1) or neurofibromin 2 (NF-2) also occur, resulting in a state where SOS1 activity is not opposed, and downstream activity in the RAS protein-mediated pathway is increased.

[0007] Therefore, the compounds of the present invention that block the interaction between SOS1 and Ras family members prevent the recirculation of KRas to its active GTP-bound form and thus may provide therapeutic benefits to a wide range of cancers, particularly Ras family member-associated cancers. The compounds of the present invention offer potential therapeutic benefits as inhibitors of SOS1-KRas interaction, which may be useful in negatively regulating KRas activity by blocking the SOS1-KRas interaction in cells for treating various forms of cancer, including Ras-associated cancers, SOS1-associated cancers, and NF1 / NF2-associated cancers. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Simanshu et al.Cell,2017.170(1):p.17-33 [Non-Patent Document 2] Matikas et al.,Crit RevOncol Hematol,2017.110:p.1-12 [Non-Patent Document 3] Sanchez-Vega et al.,Cell,2018.173:p.321-337 [Non-Patent Document 4] Li et al.,Nature Reviews Cancer,2018.18:p.767-777 [Non-Patent Document 5] Hillig,2019, Patricelli,2016, Lito,2016, Nichols,2018 [Non-Patent Document 6] Freedman et al.,Proc.Natl.Acad.Sci,USA2006.103(45):p.16692-97 [Non-Patent Document 7] Denayer, E., et al, Genes Chromosomes Cancer, 2010.49(3):p.242-52 [Non-Patent Document 8] Simanshu, D.K., Cell, 2017, Ras Proteins and their Regulators in Human Disease

Summary of the Invention

[0009] There is a need to develop new SOS1 inhibitors that block the interaction between SOS1 and members of the Ras family, prevent the recycling of KRas to its active GTP-bound form, and thus provide a therapeutic benefit for a wide range of cancers, particularly Ras-related cancers, SOS1-related cancers, and NF1 / NF2-related cancers.

[0010] In one aspect of the invention, a compound represented by formula (I),

Chemical formula

[0011] or a pharmaceutically acceptable salt thereof, wherein,

[0012] R 1 is hydrogen, hydroxyl, C1-C6 alkyl, alkoxy, -N(R 6 )2, -NR 6 C(O)R 6 , -C(O)N(R 6 )2, -SO2 alkyl, -SO2NR 6 alkyl, cycloalkyl, -Q-heterocyclyl, aryl, or heteroaryl, and cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally substituted with one or more R 2 or L-R2.

[0013] Each Q is independently a bond, O or NR 6 .

[0014] X is N or CR 7 .

[0015] Each R 2These are independently C1-C3 alkyl, oxo (i.e., C=O), hydroxy, halogen, cyano, hydroxyalkyl, haloalkyl, alkoxy, and -C(O)N(R) 6 )2, -N(R 6 )2,-SO2 alkyl,-NR 6 C(O)C1-C3 alkyl, -C(O)cycloalkyl, -C(O)C1-C3 alkyl, -C(O)heterocyclyl, aryl, heteroaryl, or heterocyclyl, where each cycloalkyl, heterocyclyl, aryl, heteroaryl, or heterocyclyl contains one or more R 11 It is being replaced by an arbitrary choice.

[0016] R 3 is hydrogen, C1-C6 alkyl, alkoxy, -N(R 10 )2, -LN(R 10 )2, cycloalkyl, haloalkyl, or heterocyclyl, where C1-C6 alkyl, cycloalkyl, and heterocyclyl each have one or more R 9 It is being replaced by an arbitrary choice.

[0017] Y is a bond or heteroarylene.

[0018] R 4 is one or more R 5 These are aryl or heteroaryl compounds that have been optionally substituted, respectively.

[0019] Each R 5 These are independently hydroxy, halogen, cyano, hydroxyalkyl, alkoxy, C1-C3 alkyl, haloalkyl, haloalkyl-OH, and -N(R) 6 )2, -LN(R 6 )2, or -SO2 alkyl.

[0020] L is a C1-C3 alkylene.

[0021] Each R 6These are independently hydrogen, C1-C3 alkyl, haloalkyl, or cycloalkyl.

[0022] R 7 It is hydrogen, cyano, or alkoxy.

[0023] R 8 These are C1-C2 alkyl or halo-C1-C2 alkyl.

[0024] Each R 9 These are independently hydroxy, halogen, amino, cyano, alkoxy, or C1-C3 alkyl.

[0025] Each R 10 These are independently hydrogen, C1-C3 alkyl, or cycloalkyl.

[0026] Each R 11 These are independently C1-C3 alkyl, halogen, or haloalkyl.

[0027] R 12 These are hydrogen, halogens, or C1-C3 alkyl groups.

[0028] In another aspect of the present invention, a pharmaceutical composition is provided comprising a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0029] In yet another embodiment, the present invention provides a method for inhibiting the activity of a Ras family member by inhibiting the association between the Ras family member and SOS1 within a cell, the method comprising contacting a cell with a compound of formula (I). In one embodiment, the contact is performed in vitro. In one embodiment, the contact is performed in vivo.

[0030] Furthermore, methods for inhibiting cell proliferation in vitro or in vivo are also provided herein, which include contacting cells with an effective amount of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof.

[0031] Furthermore, methods for treating cancer in patients requiring cancer treatment are also provided herein, which include (a) determining that the cancer is associated with a Ras family member mutation (e.g., KRas G12C-associated cancer) (e.g., determined using an assay or kit approved by a regulatory authority, e.g., FDA approved), and (b) administering to the patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof.

[0032] Furthermore, methods for treating cancer in patients requiring cancer treatment are also provided herein, which include (a) determining that the cancer is associated with the SOS1 mutation (e.g., is an SOS1-associated cancer) (e.g., determined using an assay or kit approved by a regulatory authority, e.g., FDA approved), and (b) administering to the patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof.

[0033] Furthermore, methods for treating cancer in patients requiring cancer treatment are also provided herein, which include (a) determining that the cancer is associated with an NF-1 or NF-2 loss-of-function mutation (e.g., an NF1 / NF2-associated cancer) (e.g., determined using an assay or kit approved by a regulatory authority, e.g., FDA approved), and (b) administering to the patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof.

[0034] Furthermore, the use of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a drug for inhibiting the activity of SOS1 is also provided herein.

[0035] Furthermore, the use of compounds of formula (I) as defined herein, or pharmaceutically acceptable salts or solvates thereof, in the manufacture of agents for the treatment of SOS1-related diseases or disorders is also provided herein. [Modes for carrying out the invention]

[0036] This invention relates to SOS1 inhibitors. More particularly, it relates to compounds that inhibit the activity of SOS1, pharmaceutical compositions containing therapeutically effective amounts of these compounds, and methods of using them.

[0037] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this invention pertains. All patents, patent applications, and publications referenced herein are incorporated herein by reference to the extent that they correspond to this disclosure. Terms and scopes include commonly defined definitions unless otherwise specified.

[0038] For brevity, the chemical moiety will be defined and referred to throughout primarily as a monovalent chemical moiety (e.g., alkyl, aryl, etc.). Nevertheless, such terminology may also be used to convey the corresponding multivalent moiety under appropriate structural circumstances that would be obvious to those skilled in the art. For example, while the “alkyl” moiety generally refers to a monovalent radical (e.g., CH3-CH2-), in certain circumstances the divalent linkage moiety may be “alkyl.” In such cases, those skilled in the art will understand that alkyl is a divalent radical (e.g., -CH2-CH2-) equivalent to the term “alkylene.” (Similarly, where a divalent moiety is required and it is stated that it is “aryl,” those skilled in the art will understand that the term “aryl” refers to the corresponding divalent moiety, arylene.) All atoms are understood to have the usual valency for bond formation (i.e., depending on the oxidation state of S, 4 for carbon, 3 for N, 2 for O, and 2, 4, or 6 for S).

[0039] As used herein, "KRas G12C" refers to a variant of the mammalian KRas protein containing a cysteine-glycine amino acid substitution at amino acid position 12. The assignment of amino acid codons and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116:Variant p.Gly12Cys.

[0040] As used herein, "KRas G12D" refers to a variant of the mammalian KRas protein that includes an amino acid substitution of glycine with aspartate at amino acid position 12. The assignment of amino acid codons and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116:Variant p.Gly12Asp.

[0041] As used herein, "KRas G12S" refers to a variant of the mammalian KRas protein that includes an amino acid substitution of serine to glycine at amino acid position 12. The assignment of amino acid codons and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116:Variant p.Gly12Ser.

[0042] As used herein, "KRas G12A" refers to a variant of the mammalian KRas protein that includes an amino acid substitution of glycine with alanine at amino acid position 12. The assignment of amino acid codons and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116:Variant p.Gly12Ala.

[0043] As used herein, "KRas G13D" refers to a variant of the mammalian KRas protein that includes an amino acid substitution of glycine with aspartate at amino acid position 13. The assignment of amino acid codons and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116:Variant p.Gly13Asp.

[0044] As used herein, "KRas G13C" refers to a variant of the mammalian KRas protein containing a cysteine-glycine amino acid substitution at amino acid position 13. The assignment of amino acid codons and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116:Variant p.Gly13Cys.

[0045] As used herein, "KRas Q61L" refers to a variant of the mammalian KRas protein that includes an amino acid substitution of glutamine with leucine at amino acid position 41. The assignment of amino acid codons and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116:Variant p.Gln61Leu.

[0046] As used herein, "KRas A146T" refers to a variant of the mammalian KRas protein containing an amino acid substitution of alanine with threonine at amino acid position 146. The assignment of amino acid codons and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116:Variant p.Ala146Thr.

[0047] As used herein, "KRas A146V" refers to a variant of the mammalian KRas protein that includes an amino acid substitution of alanine with valine at amino acid position 146. The assignment of amino acid codons and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116:Variant p.Ala146Val.

[0048] As used herein, "KRas A146P" refers to a variant of the mammalian KRas protein that includes an amino acid substitution of alanine with proline at amino acid position 146. The assignment of amino acid codons and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116:Variant p.Ala146Pro.

[0049] As used herein, "HRas G12C" refers to a variant of the mammalian HRas protein that includes an amino acid substitution of glycine with cysteine ​​at amino acid position 12. The assignment of amino acid codons and residue positions of human HRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01112:Variant p.Gly12Cys.

[0050] As used herein, "HRas G12D" refers to a variant of the mammalian HRas protein that includes an amino acid substitution of glycine with aspartate at amino acid position 12. The assignment of amino acid codons and residue positions of human HRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01112:Variant p.Gly12Asp.

[0051] As used herein, "HRas G12S" refers to a variant of the mammalian HRas protein that includes an amino acid substitution of serine to glycine at amino acid position 12. The assignment of amino acid codons and residue positions of human HRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01112:Variant p.Gly12Ser.

[0052] As used herein, "HRas G12A" refers to a variant of the mammalian HRas protein that includes an amino acid substitution of glycine with alanine at amino acid position 12. The assignment of amino acid codons and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01112:Variant p.Gly12Ala.

[0053] As used herein, "HRas G13D" refers to a variant of the mammalian HRas protein that includes an amino acid substitution of glycine with aspartate at amino acid position 13. The assignment of amino acid codons and residue positions of human HRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01112:Variant p.Gly13Asp.

[0054] As used herein, "HRas G13C" refers to a variant of the mammalian HRas protein that includes an amino acid substitution of glycine with cysteine ​​at amino acid position 13. The assignment of amino acid codons and residue positions of human HRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01112:Variant p.Gly13Cys.

[0055] As used herein, "HRas Q61L" refers to a variant of the mammalian HRas protein that includes an amino acid substitution of glutamine with leucine at amino acid position 41. The assignment of amino acid codons and residue positions of human HRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01112:Variant p.Gln61Leu.

[0056] As used herein, "HRas A146T" refers to a variant of the mammalian HRas protein containing an amino acid substitution of alanine with threonine at amino acid position 146. The assignment of amino acid codons and residue positions of human HRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01112:Variant p.Ala146Thr.

[0057] As used herein, "HRas A146V" refers to a variant of the mammalian HRas protein containing an amino acid substitution of alanine with valine at amino acid position 146. The assignment of amino acid codons and residue positions of human HRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01112:Variant p.Ala146Val.

[0058] As used herein, "HRas A146P" refers to a variant of the mammalian HRas protein that includes an amino acid substitution of alanine with proline at amino acid position 146. The assignment of amino acid codons and residue positions of human HRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01112:Variant p.Ala146Pro.

[0059] As used herein, “NRas G12C” refers to a variant of the mammalian NRas protein that includes an amino acid substitution of glycine with cysteine ​​at amino acid position 12. The assignment of amino acid codons and residue positions of human NRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01111:Variant p.Gly12Cys.

[0060] As used herein, “NRas G12D” refers to a variant of the mammalian NRas protein that includes an amino acid substitution of glycine with aspartate at amino acid position 12. The assignment of amino acid codons and residue positions of human NRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01111:Variant p.Gly12Asp.

[0061] As used herein, “NRas G12S” refers to a variant of the mammalian NRas protein that includes an amino acid substitution of glycine with serine at amino acid position 12. The assignment of amino acid codons and residue positions of human NRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01111:Variant p.Gly12Ser.

[0062] As used herein, “NRas G12A” refers to a variant of the mammalian NRas protein that includes an amino acid substitution of glycine with alanine at amino acid position 12. The assignment of amino acid codons and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01111:Variant p.Gly12Ala.

[0063] As used herein, "NRas G13D" refers to a variant of the mammalian NRas protein that includes an amino acid substitution of glycine with aspartate at amino acid position 13. The assignment of amino acid codons and residue positions of human NRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01111:Variant p.Gly13Asp.

[0064] As used herein, "HNRas G13C" refers to a variant of the mammalian NRas protein that includes an amino acid substitution of glycine with cysteine ​​at amino acid position 13. The assignment of amino acid codons and residue positions of human NRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01111:Variant p.Gly13Cys.

[0065] As used herein, "HRas Q61L" refers to a variant of the mammalian HRas protein that includes an amino acid substitution of glutamine with leucine at amino acid position 41. The assignment of amino acid codons and residue positions of human HRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01112:Variant p.Gln61Leu.

[0066] As used herein, "NRas A146T" refers to a variant of the mammalian NRas protein containing an amino acid substitution of alanine with threonine at amino acid position 146. The assignment of amino acid codons and residue positions of human NRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01111:Variant p.Ala146Thr.

[0067] As used herein, “NRas A146V” refers to a variant of the mammalian NRas protein containing an amino acid substitution of alanine with valine at amino acid position 146. The assignment of amino acid codons and residue positions of human NRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01111:Variant p.Ala146Val.

[0068] As used herein, "NRas A146P" refers to a variant of the mammalian NRas protein containing an amino acid substitution of alanine with proline at amino acid position 146. The assignment of amino acid codons and residue positions of human NRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01111:Variant p.Ala146Pro.

[0069] As used herein, “Ras family member” or “Ras family” refers to KRas, HRas, NRas, and their activating variants, including positions G12, G13, Q61, and A146.

[0070] As used herein, “Ras family-related disease or disorder” means a disease or disorder that is associated with, mediated by, or has an activating Ras mutation, such as those at location G12, G13, Q61, or A146. Non-exclusive examples of Ras family-related disease or disorder include KRas, HRas, or NRas G12C-related cancer, KRas, HRas, or NRas G12D-related cancer, KRas, HRas, or NRas G12S-related cancer, KRas, HRas, or NRas G12A-related cancer, KRas, HRas, or NRas G13D-related cancer, KRas, HRas, or NRas G13C-related cancer, KRas, HRas, or NRas Q61X-related cancer, KRas, HRas, or NRas A146T-related cancer, KRas, HRas, or NRas A146V-related cancer, or KRas, HRas, or NRas A146P-related cancer.

[0071] As used herein, "SOS1" refers to the mammalian son of sevenless homolog 1 (SOS1) enzyme.

[0072] As used herein, “SOS1-related disease or disorder” refers to a disease or disorder that is associated with, mediated by, or has an activated SOS1 mutation. Examples of activated SOS1 mutations include SOS1 N233S and SOS1 N233Y mutations.

[0073] As used herein, “SOS1 N233S” refers to a variant of the mammalian SOS1 protein that includes an amino acid substitution of serine to glycine at amino acid position 233. The assignment of amino acid codons and residue positions of human SOS1 is based on the amino acid sequence identified by UniProtKB / Swiss-Prot Q07889:Variant p.Gln233Ser.

[0074] As used herein, “SOS1 N233Y” refers to a variant of the mammalian SOS1 protein that includes an amino acid substitution of glutamine with tyrosine at amino acid position 233. The assignment of amino acid codons and residue positions for human SOS1 is based on the amino acid sequence identified by UniProtKB / Swiss-Prot Q07889:Variant p.Gln233Tyr.

[0075] As used herein, “SOS1 inhibitor” refers to the compound of the present invention represented by formula (I) as described herein. These compounds can negatively inhibit all or part of the interaction between SOS1 and Ras family variants or SOS1 activating mutations, thereby reducing and / or regulating the nucleotide exchange activity of the Ras family member-SOS1 complex.

[0076] As used herein, “NF-1 / NF-2 related disease or disorder” means a disease or disorder that is associated with, mediated by, or has loss-of-function mutations in the neurofibromin (NF-1) gene or the neurofibromin 2 (NF-2) gene.

[0077] As used herein, “loss-of-function mutation” means any point mutation, splice site mutation, fusion, nonsense mutation (in which an amino acid is mutated into a stop codon), in-frame or frameshift mutation (including insertions and deletions), and homozygous deletion in a gene encoding a protein in a target cell or cancer cell that results in a partial or complete loss of the presence, activity, and / or function of the encoded protein.

[0078] The term "amino" refers to -NH2.

[0079] The term "acetyl" refers to "-C(O)CH3".

[0080] As used herein, the term "acyl" refers to an alkylcarbonyl or arylcarbonyl substituent, where alkyl and aryl moieties are as defined herein.

[0081] As used herein, the term “alkyl” refers to linear and branched aliphatic groups having 1 to 12 carbon atoms. Thus, “alkyl” refers to C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 and C 12 It includes the group. Examples of alkyl groups, but are not limited to these, include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.

[0082] As used herein, the term “alkenyl” means an unsaturated linear or branched aliphatic group containing one or more carbon-carbon double bonds having 2 to 12 carbon atoms. Thus, “alkenyl” refers to C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 and C 12 It includes the group. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, and hexenyl.

[0083] As used herein, the term "alkynyl" means an unsaturated linear or branched aliphatic group containing one or more carbon-carbon triple bonds having 2 to 12 carbon atoms. Thus, "alkynyl" refers to C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 and C 12 It includes the group. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

[0084] An alkylene, alkenylene, or alkynylene group is an alkyl, alkenyl, or alkynyl group, as defined above, that is located between two other chemical groups and functions to connect them. Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, and butylene. Exemplary alkenylene groups include, but are not limited to, ethenylene, propenylene, and butenylene. Exemplary alkynylene groups include, but are not limited to, etynylene, propynylene, and butynylene.

[0085] The term "alkoxy" refers to -OC1-C6 alkyl groups.

[0086] As used herein, the term "cycloalkyl" refers to saturated and partially unsaturated cyclic hydrocarbon groups having 3 to 12 carbon atoms. Thus, "cycloalkyl" can refer to C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 and C 12 Examples include cyclic hydrocarbon groups. Examples of cycloalkyl groups, but are not limited to these, include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.

[0087] The term "heteroalkyl" refers to a chain in which one or more carbon atoms are independently substituted with O, S, or NR. x And R x This refers to alkyl groups as defined above, where the parent element is hydrogen or a C1-C3 alkyl group. Examples of heteroalkyl groups include methoxymethyl, methoxyethyl, and methoxypropyl.

[0088] The "aryl" group is a C6-C group containing 1 to 3 aromatic rings. 14 This is the aromatic part. Therefore, as an "aryl" group, it is C6, C 10 , C 13 , and C 14Examples include cyclic hydrocarbon groups. An exemplary aryl group is a C6-C 10 These are aryl groups. Specific aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and fluorenyl. The "aryl" group also includes fused polycyclic (e.g., bicyclic) ring systems in which one or more of the fused rings are non-aromatic, but at least one ring is aromatic, such as indenyl.

[0089] An "aralkyl" or "arylalkyl" group contains an aryl group covalently bonded to an alkyl group, where the alkyl portion is linked to another group via the alkyl moiety. Exemplary aralkyl groups are -(C1-C6)alkyl(C6-C10)aryl groups, which include, but are not limited to, benzyl, phenethyl, and naphthylmethyl.

[0090] A "heterocyclyl" or "heterocyclic" group has 3 to 12 atoms (3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 atoms) or 3 to 12 atoms (3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 atoms), for example, a monocyclic or bicyclic (condensed, spiro, or bridging) ring structure with 4 to 8 atoms, where one or more ring atoms are independently -C(O)-, N, NR 4 The ring atoms are O, S, or S(O)2, and the remaining ring atoms are quaternary or carbonyl carbons. Examples of heterocyclic groups include, but are not limited to, epoxy, oxylanyl, oxetanyl, azetidinyl, azilidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, thiazolidinyl, thiatanyl, dithianyl, trithianyl, azathianyl, oxathianyl, dioxolanyl, oxazolidinyl, oxazolidinyl, oxazolidinyl, decahydroquinolinyl, piperidonyl, 4-piperidonyl, thiomorpholinyl, dimethylmorpholinyl, and morpholinyl.

[0091] As used herein, "heterocyclyl" refers to a heterocyclyl group that is covalently bonded to another group via a bond.

[0092] As used herein, the term “heteroaryl” refers to a group having 5 to 14 ring atoms, preferably 5, 6, 10, 13, or 14 ring atoms, and having 6, 10, or 14 π electrons shared in a cyclic arrangement that may include 1, 2, or 3 rings, and having 1 to 3 heteroatoms, each independently being N, O, or S, in addition to carbon atoms. “Heteroaryl” also includes fused polycyclic (e.g., bicyclic, tricyclic) ring systems in which at least one of the fused rings is non-aromatic (regardless of which rings are bonded), provided that at least one ring is aromatic and at least one ring contains an N, O, or S ring atom.

[0093] Examples of heteroaryl groups include acridinyl, azosinyl, benzimidazolyl, benzofuranil, benzo[d]oxazole-2(3H)-one, 2H-benzo[b][1,4]oxazine-3(4H)-one, benzothiofuranil, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanil, clomenil, sinnolinyl, furanil, Flazanil, imidazolinil, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolidinyl, indolyl, 3H-indolyl, isobenzofuranil, isochromanil, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthilidinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxa Zolyl, oxazolidinil, pyrimidinil, phenanthrolinil, phenanthrolinil, phenazinil, phenothiazinil, phenoxathiinil, phenoxazinil, phthalazinil, piperonil, pteridinil, purinil, pyranil, pyrazinil, pyrazolidinil, pyrazolinil, pyrazolyl, pyridazinil, pyridoxazole, pyridoimidazole, pyridothiazole, pyridinil, pyridyl, pyrimidinil, pyrrolinil, 2H-pyrrolyl, pyrrrolyl, quinazolinil, quinolinil, 4H-quinolidinil, quinoxalinil, quinucrine Examples include dinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiadinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienoxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.

[0094] A "heteroaralkyl" or "heteroarylalkyl" group includes a heteroaryl group that is covalently bonded to another group via a bond. Examples of heteroalkyl groups include C1-C6 alkyl groups and heteroaryl groups having 5, 6, 9, or 10 ring atoms. Examples of heteroaralkyl groups include pyridylmethyl, pyridylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, thiazolylmethyl, thiazolylethyl, benzimidazolylmethyl, benzimidazolylethylquinazolinylmethyl, quinolinylmethyl, quinolinylethyl, benzofuranylmethyl, indolinylethylisoquinolinylmethyl, isoinodylmethyl, synnolinylmethyl, and benzothiophenylethyl. Compounds having adjacent cyclic O and / or S atoms are specifically excluded from the scope of this term.

[0095] An "arylene," "heteroarylene," or "heterocyclylene" group is a divalent aryl, heteroaryl, or heterocyclyl group, as defined above, that is located between two other chemical groups and functions to connect them.

[0096] As used herein, when a moiety (e.g., cycloalkyl, aryl, heteroaryl, heterocyclyl, urea, etc.) is described as "optionally substituted" without explicitly specifying the substituents, it means that the group has one to four, preferably one to three, and more preferably one or two, nonhydrogen substituents.

[0097] As used herein, the terms "halogen" or "halo" refer to chlorine, bromine, fluorine, or iodine.

[0098] The term "haloalkyl" refers to an alkyl chain in which one or more hydrogen atoms are replaced by halogens. Exemplary haloalkyls include trifluoromethyl, difluoromethyl, fluorochloromethyl, chloromethyl, and fluoromethyl.

[0099] The term "hydroxyalkyl" refers to -alkylene-OH.

[0100] As used herein, the terms “subject,” “individual,” or “patient” are interchangeable and refer to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, primates, and humans. In some embodiments, the patient is human. In some embodiments, the subject has experienced and / or presented with at least one symptom of a disease or disorder to be treated and / or prevented. In some embodiments, the subject has been identified or diagnosed with a cancer having a KRas G12 or G13 mutation (determined, for example, using a regulatory-approved assay or kit, e.g., FDA-approved). In some embodiments, the subject has a tumor that is positive for a KRas G12C mutation, a KRas G12D mutation, a KRas G12S mutation, a KRas G12A mutation, a KRas G13D mutation, or a KRas G13C mutation (determined, for example, using a regulatory-approved assay or kit). The subjects may have tumors that are positive for KRas G12C, KRas G12D, KRas G12S, KRas G12A, KRas G13D, or KRas G13C mutations (e.g., determined to be positive using a regulatory-approved assay or kit, e.g., FDA-approved). The subjects may have tumors that contain KRas G12C, KRas G12D, KRas G12S, KRas G12A, KRas G13D, or KRas G13C mutations (e.g., the tumors are identified as such using a regulatory-approved kit or assay, e.g., FDA-approved). In some embodiments, the subjects are suspected to have KRas G12 or G13 gene-related cancers. In some embodiments, the subject has a clinical record indicating that the subject has a tumor with a KRas G12C mutation (and optionally, the clinical record indicates that the subject should be treated with one of the compositions provided herein).

[0101] As used herein, the term “pediatric patient” refers to a patient under 16 years of age at the time of diagnosis or treatment. The term “pediatric” can be further divided into various subgroups, including neonates (from birth to 1 month of age), infants (1 month to 2 years of age), children (2 years to 12 years of age), and adolescents (12 years to 21 years of age (up to their 22nd birthday)). Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: WBSaunders Company, 1996; Rudolph AM, et al. Rudolph's Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery MD, First LR. Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994.

[0102] As used herein, an "effective amount" of a compound is an amount sufficient to negatively modulate or inhibit the activity of SOS1.

[0103] As used herein, a “therapeutically effective dose” of a compound is an amount sufficient to alleviate or reduce symptoms in any way, to halt or halt the progression of a condition, or to negatively modulate or inhibit the activity of SOS1. Such a dose may be administered as a single dose or according to a regimen, thereby being effective.

[0104] As used herein, “treatment” means any form of treatment that alleviates or favorably alters the symptoms or pathology of a condition, disorder, or disease.

[0105] As used herein, “relief” of symptoms of a particular disorder by administration of a particular compound or pharmaceutical composition means any reduction, whether permanent or temporary, persistent or transient, that may result from or be associated with the administration of the composition.

[0106] compound In one aspect of the present invention, a compound represented by formula (I) [ka]

[0107] or a pharmaceutically acceptable salt thereof

[0108] During the ceremony,

[0109] R 1 is hydrogen, hydroxyl, C1-C6 alkyl, alkoxy, -N(R 6 )2, -NR 6 C(O)R 6 ,-C(O)N(R 6 )2, -SO2alkyl, -SO2NR 6 Alkyl, cycloalkyl, -Q-heterocyclyl, aryl, or heteroaryl, where each of the cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 2 or LR 2 It is being replaced by an arbitrary choice.

[0110] Each Q can be independent, combined, O, or NR. 6 That is the case.

[0111] X is N or CR 7 That is the case.

[0112] Each R 2 These are independently C1-C3 alkyl, oxo (i.e., C=O), hydroxy, halogen, cyano, hydroxyalkyl, haloalkyl, alkoxy, and -C(O)N(R) 6 )2, -N(R 6)2,-SO2 alkyl,-NR 6 C(O)C1-C3 alkyl, -C(O)cycloalkyl, -C(O)C1-C3 alkyl, -C(O)heterocyclyl, aryl, heteroaryl, or heterocyclyl, where each cycloalkyl, heterocyclyl, aryl, heteroaryl, or heterocyclyl contains one or more R 11 It is being replaced by an arbitrary choice.

[0113] R 3 is hydrogen, C1-C6 alkyl, alkoxy, -N(R 10 )2, -LN(R 10 )2, cycloalkyl, haloalkyl, or heterocyclyl, where C1-C6 alkyl, cycloalkyl, and heterocyclyl each have one or more R 9 It is being replaced by an arbitrary choice.

[0114] Y is a bond or heteroarylene.

[0115] R 4 is one or more R 5 These are aryl or heteroaryl compounds that have been optionally substituted, respectively.

[0116] Each R 5 These are independently hydroxy, halogen, cyano, hydroxyalkyl, alkoxy, C1-C3 alkyl, haloalkyl, haloalkyl-OH, and -N(R) 6 )2, -LN(R 6 )2, or -SO2 alkyl.

[0117] L is a C1-C3 alkylene.

[0118] Each R 6 These are independently hydrogen, C1-C3 alkyl, haloalkyl, or cycloalkyl.

[0119] R 7 It is hydrogen, cyano, or alkoxy.

[0120] R 8 is C1-C2 alkyl or halo C1-C2 alkyl.

[0121] Each R 9 is independently hydroxy, halogen, amino, cyano, alkoxy, or C1-C3 alkyl.

[0122] Each R 10 is independently hydrogen, C1-C3 alkyl, or cycloalkyl.

[0123] Each R 11 is independently C1-C3 alkyl, halogen, or haloalkyl.

[0124] R 12 is hydrogen, halogen, or C1-C3 alkyl.

[0125] In one embodiment of the compound of formula (I), X is N. In certain embodiments where X is N, R 1 is alkoxy. In one embodiment, the alkoxy is methoxy.

[0126] In one embodiment of the compound of formula (I), X is N. In certain embodiments where X is N, R 1 is -Q-heterocyclyl optionally substituted with one or more R 2 . In certain embodiments, R 1 is -Q-heterocyclyl, Q is a bond, and the heterocyclyl is morpholinyl, piperazinyl, or piperazinone optionally substituted with one or more R 2 . In certain embodiments, the heterocyclyl is morpholinyl or piperazinyl, Y is a bond, and R 4 is aryl optionally substituted with one or more R 5 . In one embodiment, the heterocyclyl is morpholinyl, piperazinyl, or piperazinone, Y is heteroarylene, and R 4 is aryl optionally substituted with one or more R 5is optionally replaced aryl.

[0127] In certain embodiments of the present invention, R 1 is -Q-heterocyclyl, and the heterocyclyl is bridged morpholinyl, bridged piperazinyl, or bridged piperazinone.

[0128] In certain embodiments of the present invention, R 1 is -Q-heterocyclyl, and the heterocyclyl is a spirocyclic ring system containing two or more rings. In some of these embodiments, the spirocyclic ring system contains two rings each containing a heteroatom. In some other of these embodiments, the spirocyclic ring system contains a ring without a heteroatom (i.e., one ring containing a heteroatom and one ring without a heteroatom).

[0129] In certain embodiments of the present invention, R 1 is heteroaryl, and the heterocyclyl is optionally substituted with one or more R 2 or L-R 2 In some of these embodiments, the heteroaryl is a bicyclic or tricyclic ring system containing a non-aromatic ring in addition to one or more aromatic rings, for example, 5,6,7,8-tetrahydro-[1,2,4]triazolopyrazinyl, 5,6,7,8-tetrahydroimidazopyrazinyl, 2,4,5,6-tetrahydropyrrolopyrazolyl, 1,2,3,4-tetrahydrobenzo[4,5]imidazopyrazinyl, or 4,5,6,7-tetrahydropyrazolopyrazinyl and other bicyclic or tricyclic ring systems.

[0130] In one embodiment of the compound of formula (I), X is CR 7 In one embodiment, when X is CR 7 R 7 is cyano.

[0131] In one embodiment of the compound of formula (I), X is CR 7 In one embodiment, when X is CR 7 R7 It is hydrogen.

[0132] In one embodiment of the compound of formula (I), X is CR 7 And R 7 is hydrogen, and R 1 is hydrogen. In another embodiment, R 1 is hydroxyl. In a particular embodiment, R 1 is -N(R 6 )2. In one embodiment, R 1 is -N(R 6 )2, and each R 6 is a C1-C3 alkyl group. In one embodiment, each C1-C3 alkyl group is methyl. In other embodiments, R 1 -NR 6 C(O)R 6 In one embodiment, each C1-C3 alkyl is methyl. In one embodiment, NR 6 R 6 It is hydrogen, and C(O)R 6 R 6 It is a C1-C3 alkyl group.

[0133] In another embodiment, X is CR 7 And R 7 If R is hydrogen, 1 is -C(O)N(R 6 )2. In one embodiment, each C1-C3 alkyl is methyl. In one embodiment, each C1-C3 alkyl is hydrogen. In a particular embodiment, R 1 -SO2alkyl or -SO2NR 6 It is alkyl. In one embodiment, R1 is -SO2NR 6 It is alkyl, R 6 is hydrogen. In other embodiments, R 1 is one or more R 2 It is a cycloalkyl group optionally substituted with R. In one embodiment, the cycloalkyl group is one or more R 2These are cyclobutyl, cyclopentyl, or cyclohexyl, each optionally substituted with R. In one embodiment, cyclobutyl, cyclopentyl, or cyclohexyl is one R 2 Replaced with R 2 These are C1-C3 alkyl, alkoxy, hydroxyl, or -N(R) 6 )2. In one embodiment, R 2 is -N(R 6 )2, and each R 6 These are C1-C3 alkyl groups. In one embodiment, each C1-C3 alkyl group is methyl.

[0134] In another embodiment, X is CR 7 And R 7 If R is hydrogen, 1 is one or more R 2 A -Q-heterocyclyl optionally substituted with . In one embodiment, Q is a bond, and the heterocyclyl is morpholinyl, piperdinyl, piperazinyl, N-methylpiperazinyl, piperazinone, 1-methyl-piperazin-2-one, diazepanyl, 6,6-difluoro-1,4-diazepan-1-yl, or 4-methylthiomorpholine 1,1-dioxide. In another embodiment, Q is a bond, and the heterocyclyl is one or more R 2 These are pyrrolidinyl or tetrahydropyranil, each optionally substituted with R. In one embodiment, pyrrolidinyl or tetrahydropyranil is one R 2 Replaced with R 2 These are C1-C3 alkyl, alkoxy, hydroxyl, or -N(R) 6 )2.

[0135] In another embodiment, X is CR 7 And R 7 is hydrogen, R 1 It is a -Q-heterocyclyl, where Q is the bond and the heterocyclyl is one R 2 If it is piperazinyl substituted with R 2 is one or more R 11It is a heteroaryl that is optionally substituted with . In one embodiment, the heteroaryl is two R 11 It is a pyrazolyl substituted with each R 11 It is a C1-C3 alkyl group.

[0136] In another embodiment, X is CR 7 And R 7 is hydrogen, R 1 It is a -Q-heterocyclyl, where Q is the bond and the heterocyclyl is one R 2 If it is piperazinyl substituted with R 2 is a -C(O) cycloalkyl or -C(O) heterocycline, and each of the -C(O) cycloalkyl or -C(O) heterocycline moieties contains one or more R 11 It is optionally replaced by R. In one embodiment, 2 It is a -C(O)cycloalkyl, and cycloalkyl is one R 11 It is a cyclopropyl substituted with R 11 is a C1-C3 alkyl or haloalkyl. In one embodiment, R 2 It is a -C(O) heterocyclyl, and the heterocyclyl is oxetanil, tetrahydrofuranyl, or tetrahydropyranil.

[0137] In one embodiment, Q is a bond, and the heterocyclyl is a bicyclic heterocyclyl. In certain embodiments, the bicyclic heterocyclil is diazabicyclo[3.2.0]heptan-2-yl, (1R,5R)-2,6-diazabicyclo[3.2.0]heptan-2-yl, diazabicyclo[3.2.0]heptan-6-yl, (1R,5R)-2,6-diazabicyclo[3.2.0]heptan-6-yl, 6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-yl, 5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-yl, 1,3-dimethyl-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-yl, or (R)-2-methylhexahydropyrrolo[1,2-a]pyrazine-6(2H)-one.

[0138] In yet another embodiment, Q is O, and the heterocyclyl is azetidinyl, tetrahydrofuranyl, pyrrolidinyl, or piperidinyl.

[0139] In another embodiment, when X is CR 7 and R 7 is hydrogen, R 1 is aryl optionally substituted with one or more R 2 . In one embodiment, the aryl is phenyl optionally substituted with one or more R 2 . In a particular embodiment, the phenyl is substituted with one R 2 , and R 2 is C1-C3 alkyl, alkoxy, hydroxyl, or -N(R 6 )2. In one embodiment, R 2 is -N(R 6 )2, and each R 6 is C1-C3 alkyl. In one embodiment, each C1-C3 alkyl is methyl. In other embodiments, R 1 is heteroaryl optionally substituted with one or more R 2 . In one embodiment, the heteroaryl is pyrazolyl optionally substituted with one or more R 2 . In one embodiment, the pyrazolyl is substituted with one R 2 , and R 2 is C1-C3 alkyl, alkoxy, hydroxyl, or -N(R 6 )2. In one embodiment, R 2 is -N(R 6 )2, and each R 6 is C1-C3 alkyl. In one embodiment, each C1-C3 alkyl is methyl.

[0140] In one embodiment of the compound of formula (I), X is CR 7 , and R 7 is alkoxy. In one embodiment, the alkoxy is methoxy. When X is CR 7 and R 7In a particular embodiment where R is an alkoxy, 1 is an alkoxy. In one embodiment, R 7 The alkoxy is methoxy, and R 1 Alkoxy is methoxy.

[0141] X is N or CR 7 In certain embodiments of the compound of formula (I), Y is a heteroarylene. In one embodiment, the heteroarylene is a thiophenylene.

[0142] X is N or CR 7 In certain embodiments of the compound of formula (I), Y is a bond.

[0143] In certain embodiments of the compound of formula (I), R 4 is one or more R 5 These are aryl or heteroaryl compounds that are optionally substituted with each other. In one embodiment, R 4 is one or more R 5 It is an aryl that has been optionally substituted with R. In one embodiment, the aryl is one or more R 5 It is a phenyl compound optionally substituted with R. In a particular embodiment, the phenyl compound is one R 5 Replaced with R 5 These are C1-C4 alkyl, haloalkyl, or -LN(R 6 )2.

[0144] In one embodiment, R 5 -LN(R 6 )2, where L is methylene, and R 6 is hydrogen, and the other is R 6 is a C1-C3 alkyl group. In one embodiment, the C1-C3 alkyl group is methyl. In another embodiment, R 5 -LN(R 6 )2, where L is methylene, and each R 6 These are C1-C3 alkyl groups. In one embodiment, each of the C1-C3 alkyl groups is methyl.

[0145] R 4 In a particular embodiment where is aryl, R 4 This is two R's 5 It is a phenyl substituted with one R 5 It is a C1-C4 alkyl group, and the other R 5 is a haloalkyl. In one embodiment, the C1-C4 alkyl is methyl and the haloalkyl is trifluoromethyl. In a specific embodiment, R 4 This is two R's 5 It is a phenyl substituted with one R 5 It is a C1-C4 alkyl group, and the other R 5 -LN(R 6 )2. In one embodiment, L is methylene, and each R 6 It is a C1-C3 alkyl group.

[0146] In one embodiment of the compound of formula (I), R 3 It is hydrogen.

[0147] In certain embodiments of the compound of formula (I), R 3 is one or more R 9 The C1-C6 alkyl group is optionally substituted. In one embodiment, the C1-C6 alkyl group is methyl, ethyl, or isopropyl.

[0148] In certain embodiments of the compound of formula (I), R 3 It is an alkoxy. In one embodiment, the alkoxy is methoxy.

[0149] In certain embodiments of the compound of formula (I), R 3 is a haloalkyl group. In one embodiment, the haloalkyl group is trifluoromethyl.

[0150] In certain embodiments of the compound of formula (I), R 3 is one or more R 9It is a cycloalkyl group optionally substituted with . In one embodiment, the cycloalkyl group is cyclopropyl. In one embodiment, the cycloalkyl group is 1 R 9 Replaced with one R 9 These are halogenated amino, hydroxyl, or alkoxy compounds.

[0151] In certain embodiments of the compound of formula (I), R 3 is -N(R 10 )2. In one embodiment, each R 10 These are C1-C3 alkyl groups. In certain embodiments, each C1-C3 alkyl group is methyl.

[0152] In certain embodiments of the compound of formula (I), R 3 -LN(R 10 )2. In one embodiment, each R 10 These are C1-C3 alkyl groups. In certain embodiments, each C1-C3 alkyl group is methyl.

[0153] In certain embodiments of the compound of formula (I), R 3 is a heterocyclyl, aryl, or heteroaryl, and each of the heterocyclyl, aryl, and heteroaryl is one or more R 9 It is being replaced by an arbitrary choice.

[0154] In certain embodiments of the compound of formula (I), R 8 This is a C1-C2 alkyl group. In one embodiment, the C1-C2 alkyl group is methyl.

[0155] In certain embodiments of the compound of formula (I), R 8 This is a halo-C1-C2 alkyl group. In one embodiment, the halo-C1-C2 alkyl group is fluoromethyl, difluoromethyl, or trifluoromethyl.

[0156] In one embodiment, the compound of formula (I) is [ka]

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[0157] The compounds of formula (I) can be formulated into pharmaceutical compositions.

[0158] Pharmaceutical composition In another embodiment, the present invention provides a pharmaceutical composition comprising an SOS1 inhibitor according to the present invention and a pharmaceutically acceptable carrier, excipient, or diluent. The compounds of the present invention may be formulated by any method well known in the art and may be prepared for administration by any route, including but not limited to parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, or rectal. In certain embodiments, the compounds of the present invention are administered intravenously in a hospital. In certain other embodiments, administration may preferably be by oral route.

[0159] The characteristics of the carrier depend on the route of administration. As used herein, the term “pharmaceutically acceptable” refers to a non-toxic substance that is compatible with biological systems such as cells, cell cultures, tissues, or organisms and does not interfere with the efficacy of the biological activity of the active ingredient. Accordingly, compositions according to the present invention may contain, in addition to the inhibitor, diluents, fillers, salts, buffers, stabilizers, solubilizers, and other substances well known in the art. The preparation of pharmaceutically acceptable formulations is described, for example, in Remington's Pharmaceutical Sciences, 18th Edition, ed. A. Gennaro, Mack Publishing Co., Easton, Pa., 1990.

[0160] As used herein, the term “pharmaceutically acceptable salt” refers to a salt of the compound identified above that retains the desired biological activity and exhibits minimal or no unwanted toxicity. Examples of such salts include, but are not limited to, acid addition salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.), as well as salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid. The compounds can also be administered as pharmaceutically acceptable quaternary salts known to those skilled in the art, which specifically comprise quaternary ammonium salts of the formula --NR+Z-, where R is hydrogen, alkyl, or benzyl, and Z is a counterion comprising chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate salts (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamate, mandelate, benzylate, and diphenylacetate).

[0161] The active compound is contained in a pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver a therapeutically effective dose to the patient without causing serious toxicity to the patient being treated. For all of the above conditions, the dose of the active compound is in the range of about 0.01 to 300 mg / kg per day, preferably 0.1 to 100 mg / kg, and more generally in the range of 0.5 to about 25 mg per kilogram of body weight of the recipient per day. A typical topical dose is in the range of 0.01 to 3 wt / wt% in a suitable carrier. The effective dose range of a pharmaceutically acceptable derivative can be calculated based on the weight of the parent compound being delivered. If the derivative is active on its own, the effective dose can be estimated as described above using the weight of the derivative or by other means known to those skilled in the art.

[0162] A pharmaceutical composition containing the compound of the present invention may be used in the methods described herein.

[0163] How to use In yet another aspect, the present invention provides a method for inhibiting SOS1 activity in cells, comprising contacting cells in which inhibition of SOS1 activity is desired with an effective amount of the compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the compound or a pharmaceutically acceptable salt thereof.

[0164] The compositions and methods provided herein are deemed particularly useful for inhibiting SOS1 activity in cells. In one embodiment, cells in which inhibition of SOS1 activity is desired are contacted in vivo with a therapeutically effective amount of the compound of formula (I) to negatively modulate SOS1 activity. In other embodiments, a pharmaceutical composition containing a therapeutically effective amount of a pharmaceutically acceptable salt or compound of formula (I) may be used. In one embodiment, the cells harbor an activating mutation in a Ras family member such as KRas, HRas, or NRas. In one embodiment, the cells have abnormal SOS1 activity. In one embodiment, the abnormal SOS1 activity is a result of an SOS1 activating mutation. In one embodiment, the SOS1 activating mutation is an N233S or N233Y mutation. In one embodiment, the cells have abnormal NF-1 or NF-2 activity. In one embodiment, the abnormal NF-1 or NF-2 activity is a result of an NF-1 or NF-2 activating mutation.

[0165] By negatively modulating SOS1 activity, the method is designed to block interactions between SOS1 and Ras family members, increase GTP loading of RAS proteins, thereby reducing or inhibiting GTP nucleotide exchange, immobilizing Ras family members in a GDP-bound inactive state, and resulting in inhibition of downstream Ras-mediated signaling. Cells may be contacted in single or multiple doses according to a specific therapeutic scheme to influence the desired negative modulation of SOS1.

[0166] In another embodiment, a method for treating cancer is provided, comprising administering to a patient having cancer a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof. In one embodiment, the cancer is a Ras family-related cancer. In one embodiment, the cancer is an SOS-1-related cancer. In one embodiment, the cancer is an NF-1 / NF-2-related cancer.

[0167] The compositions and methods provided herein can be used to treat a wide variety of cancers, including, for example, prostate cancer, breast cancer, brain tumors, skin cancer, cervical cancer, and testicular cancer. More specifically, cancers that can be treated with the compositions and methods of the present invention include, but are not limited to, astrocytoma, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, hepatocellular carcinoma, laryngeal cancer, lung cancer, oral cancer, ovarian cancer, prostate cancer, and thyroid cancer, as well as sarcomas and other tumor types. More specifically, these compounds are found in: heart: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyomas, fibromas, lipomas, and teratomas; lungs: bronchogenic carcinomas (squamous cell carcinoma, anaplastic small cell carcinoma, anaplastic large cell carcinoma, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; gastrointestinal tract: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyoma, lymphoma), stomach (carcinoma, lymphoma, leiomyoma), pancreas (ductal Adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, VIP-producing tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, chorioadenoma, hamartoma, leiomyoma); urogenital tract: kidney (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (Adenocarcinoma, sarcoma), testes (seminoma, teratoma, fetal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); liver: hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; biliary tract: gallbladder cancer, ampulla cancer, cholangiocarcinoma; bone: osteogenic sarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant Giant cell tumors: chordoma, osteochondroma (osteochondrial exostosis), benign chordoma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor; nervous system: skull (osteoma, hemangioma, granuloma, xanthomas, osteoosteitis), meningioma (meningioma, meningiosarcoma, glioma), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ tumor (pineal glandoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal neurofibroma, meningioma, glioma, sarcoma);Gynecology: Uterus (endometrial cancer), cervix (cervical cancer, preneoplastic cervical dysplasia), ovaries (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified cancer), granulosa-theca cell tumor, Sertoli-Leydig cell tumor, undifferentiated germ cell tumor, malignant teratoma)), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, staphyloid sarcoma (embryonic rhabdomyosarcoma)), fallopian tubes (carcinoma); Hematology: blood It can be used to treat: fluids (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin lymphoma (malignant lymphoma); skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevus moles, lipomas, hemangiomas, dermatofibromas, keloids, psoriasis; and adrenal glands: neuroblastoma. In certain embodiments, the cancer is diffuse large B-cell lymphoma (DLBCL).

[0168] In one embodiment, the cancer is a Ras family-related cancer, such as a KRas, NRas, or HRas-related cancer. In a specific embodiment, the Ras family-related cancer is a non-small cell lung cancer or pancreatic cancer. In one embodiment, the cancer is an SOS1-related cancer. In a specific embodiment, the SOS1-related cancer is a lung adenocarcinoma, embryonal rhabdomyosarcoma, Sertoli cell testicular tumor, and granular cell tumor of the skin. In one embodiment, the cancer is an NF-1-related cancer.

[0169] The dosage concentration and route of administration to the patient will vary depending on the cancer being treated. The compound, its pharmaceutically acceptable salts, and pharmaceutical compositions containing such compound and salts may also be administered co-administered with other antineoplastic compounds, such as chemotherapeutic agents, or used as adjuvants pre- or post-operatively in combination with other treatments such as irradiation or surgical intervention.

[0170] General reaction scheme, intermediates, and examples General reaction scheme The compounds of the present invention may be prepared using commercially available reagents and intermediates in the synthesis methods and reaction schemes described herein, or they may be prepared using other reagents and conventional methods well known to those skilled in the art.

[0171] For example, the compound and intermediates for preparing the compound of formula (I) of the present invention can be prepared according to general reaction schemes I to VI.

[0172] [ka] In the general reaction scheme I, compound 5 is an example of formula (I). In this general reaction scheme I, compound 1 reacts with an amine such as intermediate 2, and this reaction can be a nucleophilic substitution or metal-catalyzed reaction producing, for example, compound 3. Compound 3 can then undergo a metal-catalyzed reaction with a coupling partner such as a boronic acid derivative, Y-R34, in the presence of a suitable base, such as sodium carbonate, to form the title compound 5.

[0173] [ka] In the general reaction scheme II, compound 5 is an example of formula (I). In this general reaction scheme II, 6 reacts with an amine such as intermediate 2, and this reaction can be a nucleophilic substitution or metal-catalyzed reaction producing, for example, compound 7. Next, compound 7 is reacted with a boronic acid derivative, YR, in the presence of a suitable base, for example, sodium carbonate. 1 The title compound 5 can be formed through a metal-catalyzed reaction with a coupling partner such as 8.

[0174] [ka] In the general reaction scheme III, compound 5 is an example of formula (I). In this general reaction scheme III, compound 7 is an alcohol or amine, HR, in the presence of a suitable base, such as cesium carbonate. 1The title compound 5 can be formed by either a metal-catalyzed reaction with a coupling partner such as 9, or by nucleophilic substitution resulting therefrom.

[0175] [ka] In the general reaction scheme IV, compound 5 is an example of formula (I). In this general reaction scheme IV, compound 10 reacts with an amine such as intermediate 2, and this reaction can be a nucleophilic substitution or metal-catalyzed reaction that produces compound 5, for example.

[0176] [ka] In the general reaction scheme V, compound 5 is an example of formula (I). In this general reaction scheme V, 11 reacts with an amine such as intermediate 2, and this reaction can be a nucleophilic substitution or metal-catalyzed reaction producing, for example, compound 12. Next, compound 12 is reacted with a boronic acid derivative, YR, in the presence of a suitable base, for example, sodium carbonate. 3 Compound 7 can be formed by a metal-catalyzed reaction with a coupling partner such as 4. Next, compound 7 can be reacted with a boronic acid derivative, YR, in the presence of a suitable base, for example, sodium carbonate. 1 The title compound 5 can be formed through a metal-catalyzed reaction with a coupling partner such as 8.

[0177] [ka] In the general reaction scheme VI, compound 5 is an example of formula (I). In this general reaction scheme VI, compound 13 is coupled with an alcohol, halide, tosylate, or mesylate XR in the presence of a suitable base or coupling partner, such as cesium carbonate or diethyl azodicarboxylate. 1 It can participate in substitution reactions with coupling partners such as 14 to form the title compound 5.

[0178] The compounds of the present invention may be prepared using the following intermediates.

[0179] Intermediate A [ka] Step A: To a mixture of 1-(2-bromophenyl)-N-methylmethaneamine (6.50 g, 32.5 mmol, 1 equivalent) in THF (70.0 mL), Boc2O (7.80 g, 35.7 mmol, 8.21 mL, 1.10 equivalents) was added dropwise at 25°C, and the mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated directly under vacuum to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 10 / 1) to obtain tert-butyl(2-bromobenzyl)(methyl)carbamate (7.50 g, 25.0 mmol, 76.9% yield) as a colorless oil.

[0180] 1 H NMR (400MHz, CDCl3) δ 7.55(br d,J=8.0Hz,1H), 7.34-7.28(m,1H), 7.22-7.08(m,2H), 4.61-4.42(m,2H), 2.94-2.78(m,3H), 1.60-1.33(m,9H).

[0181] Step B: A mixture of tert-butyl(2-bromobenzyl)(methyl)carbamate (7.00 g, 23.3 mmol, 1.00 equivalent), bis(pinacolate)diborone (8.88 g, 35.0 mmol, 1.50 equivalent), Pd(dppf)Cl2 (1.71 g, 2.33 mmol, 0.10 equivalent), and potassium acetate (5.72 g, 58.3 mmol, 2.50 equivalent) in dioxane (80.0 mL) was degassed, purged three times with nitrogen, and then stirred under a nitrogen atmosphere at 110°C for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was then purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to obtain tert-butylmethyl (2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (8.00 g, 23.0 mmol, 98.8% yield) as a colorless oil.

[0182] 1 H NMR(400MHz,CDCl3)δ 7.82(br d,J=7.2Hz,1H), 7.48-7.37(m,1H), 7.27-7.21(m,2H), 4.85-4.63(m,2H), 2.92-2.73(m 3H), 1.54-1.41(m,9H), 1.35(s,12H).

[0183] Intermediate B [ka] Step A: Ti(OEt)4 (8.09 g, 35.5 mmol, 7.35 mL, 2.00 equivalent) was added to a solution of 1-(4-bromothiophen-2-yl)ethane-1-one (4.00 g, 19.5 mmol, 1.10 equivalent) and 2-methylpropan-2-sulfinamide (2.15 g, 17.7 mmol, 1.00 equivalent) in THF (56.0 mL). The mixture was stirred at 70°C for 2 hours. The mixture was poured into water (15.0 mL) and stirred for 5 minutes. The suspension was filtered, and the filtrate was concentrated under vacuum to obtain the residue. The residue was washed with petroleum ether / ethyl acetate = 5 / 1 (10 mL), filtered, and the filter cake was collected and dried under vacuum to obtain N-(1-(4-bromothiophen-2-yl)ethylidene)-2-methylpropane-2-sulfinamide (3.00 g, 9.73 mmol, 54.9% yield) as a yellow solid.

[0184] 1 H NMR (400MHz, CDCl3) δ 7.43(d,J=1.2Hz,1H), 7.41(d,J=1.2Hz,1H), 2.72(s,3H), 1.30(s,9H).

[0185] Step B: To a solution of N-(1-(4-bromothiophen-2-yl)ethylidene)-2-methylpropane-2-sulfinamide (3.70 g, 12.0 mmol, 1.00 equivalent) in THF (40.0 mL), sodium borohydride (1.36 g, 36.0 mmol, 3.00 equivalent) was added at 0°C. The reaction mixture was slowly warmed to 25°C and stirred for 2 hours. The mixture was poured into ice water (15.0 mL) and stirred at 0°C for 5 minutes. The aqueous phase was extracted with ethyl acetate (30.0 mL x 3). The combined organic phases were washed with brine (30.0 mL x 3), dried on anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain N-(1-(4-bromothiophen-2-yl)ethyl)-2-methylpropane-2-sulfinamide (3.60 g, 9.51 mmol, 79.3% yield, 82.0% purity) as a yellow oil.

[0186] 1H NMR(400MHz, CDCl3)δ 7.15(s,1H), 6.98-6.96(s,1H), 4.81-4.75(m,1H), 3.55(br d,J=3.6Hz,1H), 1.59(d,J=6.4Hz,3H), 1.24(s,9H).

[0187] Step C: To a solution of N-(1-(4-bromothiophen-2-yl)ethyl)-2-methylpropane-2-sulfinamide (3.00 g, 9.67 mmol, 1.00 equivalent) and tert-butylmethyl (2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (5.04 g, 14.5 mmol, 1.50 equivalent) in dioxane (35.0 mL) and water (8.00 mL), Pd(PPh3)4 (1.12 g, 967 μmol, 0.10 equivalent) and cesium carbonate (9.45 g, 29.01 mmol, 3.00 equivalent) were added under a nitrogen atmosphere. The mixture was stirred under a nitrogen atmosphere at 110°C for 2 hours. The mixture was filtered, and the filtrate was concentrated under vacuum to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to obtain tert-butyl(2-(5-(1-((tert-butylsulfinyl)amino)ethyl)thiophen-3-yl)benzyl)(methyl)carbamate (1.40 g, 3.11 mmol, 32.1% yield) as a yellow oil. LCMS[M+1]:451.2.

[0188] Step D: To a solution of tert-butyl(2-(5-(1-((tert-butylsulfinyl)amino)ethyl)thiophen-3-yl)benzyl)(methyl)carbamate (1.40 g, 4.88 mmol, 1.00 equivalent) in THF (15.0 mL) and water (5.00 mL), iodine (232 mg, 1.46 mmol, 295 μL, 0.30 equivalent) was added. The mixture was stirred at 50°C for 30 minutes. The residue was poured into saturated sodium sulfite aqueous solution (30.0 mL) and stirred for 5 minutes. The aqueous phase was extracted with ethyl acetate (15.0 mL x 2). The combined organic phases were washed with brine (30.0 mL x 2), dried on anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain tert-butyl(2-(5-(1-aminoethyl)thiophen-3-yl)benzyl)(methyl)carbamate (1.20 g, crude) as a yellow oil.

[0189] 1 H NMR(400MHz,CDCl3)δ 7.36-7.28(m,3H), 7.26-7.22(m,1H), 7.01(s,1H), 6.91(br s,1H), 4.49(br d,J=19.2Hz,2H), 4.40(q,J=6.4Hz,1H), 2.72(br d,J=19.2Hz,3H), 1.53(d,J=6.4Hz,3H), 1.51-1.40(m,9H).

[0190] Intermediates C and D [ka] Step A: To a solution of 4-bromothiophene-2-carbaldehyde (20.0 g, 104 mmol, 1.00 equivalent) and (R)-2-methylpropane-2-sulfinamide (12.1 g, 99.5 mmol, 0.95 equivalent) in THF (200 mL), titanium(IV) ethoxide (47.8 g, 209 mmol, 43.4 mL, 2.00 equivalent) was added. The reaction mixture was stirred at 25°C for 1 hour. Next, the mixture was poured into water (20.0 mL) and stirred for 5 minutes to obtain a suspension. The suspension was filtered, and the filtered liquid was concentrated under vacuum to obtain (R,E)-N-((4-bromothiophene-2-yl)methylene)-2-methylpropane-2-sulfinamide (20.0 g, crude) as a yellow oil. LCMS[M+1]: 295.8.

[0191] Step B: To a solution of (R,E)-N-((4-bromothiophen-2-yl)methylene)-2-methylpropane-2-sulfinamide (600 mg, 2.04 mmol, 1.00 equivalent) in THF (200 mL), methylmagnesium bromide (3.00 M, 2.04 mL, 3.00 equivalent) was added dropwise at 0°C. The reaction mixture was then stirred at 25°C for 1 hour. Saturated ammonium chloride aqueous solution (3.00 mL) was added to the reaction mixture and stirred for 5 minutes. The aqueous phase was extracted with ethyl acetate (3.00 mL x 2), the combined organic phase was washed with brine (3.00 mL x 2), dried on anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 1 / 1) to obtain (R)-N-((S)-1-(4-bromothiophen-2-yl)ethyl)-2-methylpropane-2-sulfinamide (first elution, intermediate C) (120 mg, 19.0% yield) as yellow oil, and (R)-N-((R)-1-(4-bromothiophen-2-yl)ethyl)-2-methylpropane-2-sulfinamide (second elution, intermediate D) (150 mg, 483 μmol, 23.7% yield) as yellow oil.

[0192] Intermediate C: 1H NMR (400MHz, CDCl3) δ7.15(d,J=1.6Hz,1H),6.97(s,1H),4.81-4.75(m,1H),3.51(brd,J=3.2Hz,1H),1.59(d,J=6.8Hz,3H),1.24(s,9H).

[0193] Intermediate D: 1 H NMR (400MHz, CDCl3) δ7.14(d,J=1.6Hz,1H),6.89(s,1H),4.81-4.74(m,1H),3.39(brd,J=5.6Hz,1H),1.65(d,J=6.8Hz,3H),1.25(s,9H).

[0194] Intermediate E [ka] Step A: To a solution of (R)-N-((R)-1-(4-bromothiophen-2-yl)ethyl)-2-methylpropane-2-sulfinamide (150 mg, 483 μmol, 1.00 equivalent) and tert-butylmethyl (2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (168 mg, 483 μmol, 1.00 equivalent) in dioxane (1.00 mL) and water (0.20 mL), Pd(PPh3)4 (55.9 mg, 48.3 μmol, 0.10 equivalent) and cesium carbonate (473 mg, 1.45 mmol, 3.00 equivalent) was added under a nitrogen atmosphere. The reaction mixture was stirred under a nitrogen atmosphere at 110°C for 2 hours, then to 25°C, and concentrated under vacuum to obtain the residue. The residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 1 / 1) to obtain tert-butyl(2-(5-((R)-1-(((R)-tert-butylsulfinyl)amino)ethyl)thiophen-3-yl)benzyl)(methyl)carbamate (120 mg, 266 μmol, 55.1% yield) as a white solid. LCMS[M+1] = 451.1.

[0195] 1H NMR(400MHz,CDCl3)δ 7.37-7.29(m,3H), 7.25(s,1H), 7.06(s,1H), 6.95(br s,1H), 4.88-4.81(m,1H), 4.48(br d,J=16.0Hz,2H), 3.44(br d,J=6.0Hz,1H), 2.73(br d,J=12.8Hz,3H), 1.71(d,J=6.4Hz,3H), 1.27(s,9H), 1.25(s,9H).

[0196] Step B: To a solution of tert-butyl(2-(5-((R)-1-(((R)-tert-butylsulfinyl)amino)ethyl)thiophen-3-yl)benzyl)(methyl)carbamate (120 mg, 266 μmol, 1.00 equivalent) in THF (1.00 mL) and water (0.20 mL), iodine (20.3 mg, 79.9 μmol, 16.1 μL, 0.30 equivalent) was added, and the reaction mixture was stirred at 50°C for 1 hour. Next, the reaction mixture was cooled to 25°C, poured into saturated sodium sulfite aqueous solution (2.00 mL), and stirred for 5 minutes. The aqueous phase was extracted with ethyl acetate (3.00 mL x 3), the combined organic phase was washed with brine (3.00 mL x 3), dried on anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75×30mm×3um; mobile phase: [water (0.1% TFA)-ACN]; B%: 28%~38%) to obtain tert-butyl(R)-(2-(5-(1-aminoethyl)thiophen-3-yl)benzyl)(methyl)carbamate (40.0 mg, 113 μmol, 42.3% yield, 97.5% purity) as a white oil.

[0197] 1 H NMR(400MHz,CD3OD)δ 7.41-7.23(m,6H), 4.84-4.79(m,1H), 4.48(s,2H), 2.73(s,3H), 1.76(d,J=6.8Hz,3H), 1.51-1.36(m,9H).

[0198] Intermediate F [ka] Step A: To a solution of (R)-N-((S)-1-(4-bromothiophen-2-yl)ethyl)-2-methylpropane-2-sulfinamide (100 mg, 322 μmol, 1.00 equivalent) and tert-butylmethyl (2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (112 mg, 322 μmol, 1.00 equivalent) in dioxane (1.00 mL) and water (0.20 mL), Pd(PPh3)4 (37.2 mg, 32.2 μmol, 0.10 equivalent) and cesium carbonate (315 mg, 967 µmol, 3.00 equivalent) were added under a nitrogen atmosphere. The reaction mixture was stirred at 110 °C for 2 hours, then cooled to 25 °C, and concentrated under vacuum to obtain the residue. The residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 1 / 1) to obtain tert-butyl(2-(5-((S)-1-(((R)-tert-butylsulfinyl)amino)ethyl)thiophen-3-yl)benzyl)(methyl)carbamate (100 mg, 266 μmol, 68.9% yield) as a yellow oil. LCMS[M+1] = 451.1.

[0199] 1 H NMR(400MHz,CDCl3)δ 7.37-7.28(m,3H), 7.26-7.22(m,1H), 7.07(d,J=1.2Hz,1H), 7.03(br s,1H), 4.90-4.83(m,1H), 4.55-4.41(m,2H), 3.71-3.55(m,1H), 2.80-2.65(m,3H), 1.64(d,J=6.8Hz,3H), 1.52-1.41(m,9H), 1.26(s,9H).

[0200] Step B: To a solution of tert-butyl(2-(5-((S)-1-(((R)-tert-butylsulfinyl)aminoethyl)thiophen-3-yl)benzyl)(methyl)carbamate (100 mg, 266 μmol, 1.00 equivalent) in THF (1.00 mL) and water (0.20 mL), iodine (16.9 mg, 66.6 μmol, 13.4 μL, 0.30 equivalent) was added. The reaction mixture was stirred at 50°C for 1 hour, then cooled to 25°C, poured into saturated sodium sulfite aqueous solution (2.00 mL), and stirred for 5 minutes. The aqueous phase was extracted with ethyl acetate (3.00 mL x 3), the combined organic phase was washed with brine (3.00 mL x 3), dried on anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150×25mm×10um; mobile phase: [water (0.1% TFA)-ACN]; B%: 24%~54%) to obtain tert-butyl(S)-(2-(5-(1-aminoethyl)thiophen-3-yl)benzyl)(methyl)carbamate (45.0 mg, 97.7 μmol, 44.0% yield, TFA salt) as a white oil. LCMS[M+1] = 347.2.

[0201] 1 H NMR(400MHz,CD3OD)δ 7.40(d,J=1.2Hz,1H), 7.38-7.22(m,5H), 4.82-4.80(br s,1H), 4.48(s,2H), 2.73(s,3H), 1.75(d,J=6.8Hz,3H), 1.50-1.35(m,9H).

[0202] intermediate G [ka] Step A: Titanium(IV) ethoxide (727 mg, 3.19 mmol, 661 μL, 2.00 equivalent) was added to a solution of 2-methyl-3-(trifluoromethyl)benzaldehyde (300 mg, 1.59 mmol, 1.00 equivalent) and 2-methylpropane-2-sulfinamide (213 mg, 1.75 mmol, 1.10 equivalent) in THF (5.00 mL). The reaction mixture was stirred at 25°C for 12 hours. The reaction mixture was poured into water (2.00 mL) and stirred for 5 minutes to obtain a suspension. The suspension was filtered and concentrated under vacuum to obtain 2-methyl-N-(2-methyl-3-(trifluoromethyl)benzylidene)propane-2-sulfinamide (360 mg, 1.24 mmol, 77.5% yield) as a white solid.

[0203] 1 H NMR (400MHz, CDCl3) δ=8.98(s,1H), 8.13(d,J=7.6Hz,1H), 7.78(d,J=7.6Hz,1H), 7.40(t,J=7.6Hz,1H), 2.70(d,J=0.8Hz,3H), 1.29(s,9H).

[0204] Step B: To a solution of 2-methyl-N-(2-methyl-3-(trifluoromethyl)benzylidene)propan-2-sulfinamide (185 mg, 635 μmol, 1.00 equivalent) in THF (5.00 mL), methylmagnesium bromide (227 mg, 3.00 M, 635 μL, 3.00 equivalent) was added dropwise at 0°C under a nitrogen atmosphere. The reaction mixture was stirred at 25°C for 3 hours, and then slowly treated with saturated ammonium chloride solution (10.0 mL). The organic layer and aqueous phase were separated, and the aqueous phase was extracted with ethyl acetate (5.00 mL x 3). The combined organic layers were washed with brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to obtain 2-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)propan-2-sulfinamide (150 mg, 488.0 μmol, 76.8% yield) as a yellow solid.

[0205] 1 H NMR (400MHz, CDCl3)δ=7.65-7.54(m,4H), 7.35-7.28(m,2H), 5.00-4.87(m,2H), 2.49(s,6H), 1.54-1.50(m,6H), 1.26-1.24(m,9H), 1.22(s,9H).

[0206] Step C: The mixture was stirred at 25°C for 1 hour in a solution of 2-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)propan-2-sulfinamide (150 mg, 488.0 μmol, 1.00 equivalent) in HCl (4.0 M in dioxane, 1.00 mL). The reaction mixture was filtered, and the filter cake was concentrated under vacuum to obtain 1-(2-methyl-3-(trifluoromethyl)phenyl)ethane-1-amine (45.0 mg, 38.5% yield) as a red solid. LCMS[M+1] = 204.3.

[0207] 1 H NMR (400MHz, CD3OD) δ=7.78-7.65(m,2H), 7.56-7.48(m,1H), 4.93-4.89(m,1H), 2.52(d,J=0.8Hz,3H), 1.63(d,J=6.8Hz,3H).

[0208] Intermediate H [ka] Step A: Titanium(IV) ethoxide (18.1 g, 79.1 mmol, 16.4 mL, 2.00 equivalent) was added to a solution of 1-(2-methyl-3-(trifluoromethyl)phenyl)ethane-1-one (8.00 g, 39.6 mmol, 1.00 equivalent) and (S)-2-methylpropan-2-sulfinamide (5.28 g, 43.5 mmol, 1.10 equivalent) in THF (80.0 mL). The reaction mixture was stirred at 70°C for 2 hours. The reaction mixture was cooled to 25°C, poured into ice water (w / w=1 / 1) (80.0 mL), and stirred for 15 minutes to obtain a suspension. The suspension was filtered, and the filtrate was extracted with ethyl acetate (50.0 mL × 3). The combined organic phases were washed with brine (30.0 mL × 3), dried on anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1~3 / 1) to obtain (S)-2-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethylidene)propan-2-sulfinamide (8.00 g, 26.2 mmol, 66.2% yield) as a yellow oil. LCMS[M+1]:306.2.

[0209] 1 H NMR(400MHz,CD3OD)δ 7.74(br t,J=7.2Hz,2H), 7.57-7.51(m,1H), 7.46(br t,J=7.6Hz,2H), 7.43-7.30(m,1H), 2.72(s,3H), 2.54(J=6.8Hz,3H), 2.48(s,3H), 2.40(br d,J=16.0Hz,3H), 1.31(s,9H), 1.24(br d,J=12.4Hz,9H).

[0210] Step B: To a solution of S)-2-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethylidene)propan-2-sulfinamide (8.00 g, 26.2 mmol, 1.00 equivalent) in THF (80.0 mL), L-selectlide (7.47 g, 39.3 mmol, 8.59 mL, 1.50 equivalent) was added dropwise at -78°C. The reaction mixture was stirred at -78°C for 2 hours. Water was added dropwise to the reaction mixture (10.0 mL) at 0°C, and the resulting mixture was stirred for 5 minutes. The aqueous phase was extracted with ethyl acetate (30.0 mL × 3). The combined organic phases were washed with brine (30.0 mL × 2), dried on anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1~3 / 1) to obtain (S)-2-methyl-N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)propan-2-sulfinamide (3.50 g, 11.4 mmol, 43.5% yield) as a yellow oil. LCMS[M+1]: 308.0.

[0211] 1 H NMR(400MHz,CD3OD)δ=7.70(d,J=8.0Hz,1H), 7.57(d,J=7.6Hz,1H), 7.39-7.33(m, 1H), 4.94-4.88(m,1H), 2.48(d,J=1.2Hz,3H), 1.54(d,J=6.4Hz,3H), 1.20(s,9H).

[0212] Step C: A solution of S)-2-methyl-N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)propan-2-sulfinamide (1.30 g, 4.23 mmol, 1.00 equivalent) in HCl (4 M in dioxane, 15.0 mL) was stirred at 25°C for 30 minutes. The reaction mixture was filtered, and the filter cake was dried under vacuum to obtain (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethane-1-amine (700 mg, 2.89 mmol, 68.4% yield, 99.1% purity, hydrochloride) as a white solid. LCMS[M+H]: 204.0.

[0213] 1 H NMR (400MHz, CD3OD) δ=7.73(t,J=7.6Hz,2H), 7.54-7.49(m,1H), 4.92-4.88(m,1H), 2.52(d,J=0.8Hz,3H), 1.62(d,J=6.8Hz,3H).

[0214] Intermediate I [ka] Step A: To a solution of 1-(5-bromothiophen-2-yl)ethane-1-one (11.0 g, 53.6 mmol, 1.00 equivalent) in THF (120 mL), 2-methylpropan-2-sulfinamide (8.45 g, 69.7 mmol, 1.30 equivalent) and titanium(IV) ethoxide (24.5 g, 107 mmol, 22.3 mL, 2.00 equivalent) were added, and the reaction mixture was stirred at 75°C for 12 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25°C, concentrated under vacuum to obtain a residue, diluted with water (200 mL) and ethyl acetate (200 mL), filtered, and the filtrate was extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain N-(1-(5-bromothiophen-2-yl)ethylidene)-2-methylpropane-2-sulfinamide (16.0 g, crude) as a yellow solid. LCMS[M+1]: 308.0.

[0215] Step B: To a solution of N-(1-(5-bromothiophen-2-yl)ethylidene)-2-methylpropane-2-sulfinamide (16.0 g, 51.9 mmol, 1.00 equivalent) in THF (150 mL), sodium borohydride (3.93 g, 104 mmol, 2.00 equivalent) was added at 0°C, and the reaction mixture was stirred at 20°C for 1 hour. Saturated sodium bicarbonate aqueous solution (20.0 mL) was added dropwise to the reaction mixture, then the mixture was diluted with water (200 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 30 / 1~2 / 1) to obtain N-(1-(5-bromothiophen-2-yl)ethyl)-2-methylpropane-2-sulfinamide (12.0 g, 38.7 mmol, 74.5% yield) as a yellow oil. LCMS[M+1]: 309.9.

[0216] Intermediate J [ka] Step A: To a solution of 1-(5-bromothiophen-2-yl)ethane-1-one (10.0 g, 48.8 mmol, 1.00 equivalent) and (R)-2-methylpropan-2-sulfinamide (7.68 g, 63.4 mmol, 1.30 equivalent) in THF (120 mL), titanium(IV) ethoxide (22.3 g, 97.5 mmol, 20.2 mL, 2.00 equivalent) was added, and the reaction mixture was stirred at 70°C for 12 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25°C, diluted with water (200 mL) and ethyl acetate (100 mL) to obtain a suspension, filtered, and the filtrate was extracted with ethyl acetate (100 mL x 3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain (R,E)-N-(1-(5-bromothiophen-2-yl)ethylidene)-2-methylpropane-2-sulfinamide (13.0 g, crude) as a brown oil. LCMS[M+1]:308.2.

[0217] 1H NMR (400MHz, CDCl3) δ=7.23(d,J=4.0Hz,1H), 7.04(d,J=4.0Hz,1H), 2.67(s,3H), 1.28(s,9H).

[0218] Step B: To a solution of (R,E)-N-(1-(5-bromothiophen-2-yl)ethylidene)-2-methylpropane-2-sulfinamide (13.0 g, 42.2 mmol, 1.00 equivalent) in THF (150 mL), sodium borohydride (4.79 g, 127 mmol, 3.00 equivalent) was added at 0°C. The reaction mixture was stirred under a nitrogen atmosphere at 20°C for 2 hours. Saturated sodium bicarbonate aqueous solution (20.0 mL) was added dropwise to the mixture, diluted with water (200 mL), and the resulting aqueous solution was extracted with ethyl acetate (100 mL x 3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 30 / 1~2 / 1) to obtain (R)-N-((R)-1-(5-bromothiophen-2-yl)ethyl)-2-methylpropane-2-sulfinamide (6.00 g, 17.4 mmol, 41.3% yield, 90.0% purity) as a brown solid. LCMS[M+1]: 309.9.

[0219] 1 H NMR (400MHz, CDCl3) δ=6.90(d,J=3.6Hz,1H), 6.80(d,J=3.6Hz,1H), 4.84-4.66(m,1H), 3.50(d,J=2.8Hz,1H), 1.57(d,J=6.4Hz,3H), 1.23(s,9H).

[0220] Step C: To a solution of (R)-N-((R)-1-(5-bromothiophen-2-yl)ethyl)-2-methylpropane-2-sulfinamide (2.00 g, 6.45 mmol, 1.00 equivalent) and tert-butylmethyl (2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (2.69 g, 7.74 mmol, 1.20 equivalent) in dioxane (20.0 mL) and water (2.00 mL), cesium carbonate (6.30 g, 19.3 mmol, 3.00 equivalent) and Pd(PPh3)4 (745 mg, 645 μmol, 0.10 equivalent) were added under a nitrogen atmosphere. The reaction mixture was stirred under a nitrogen atmosphere at 110°C for 2 hours. Next, the reaction mixture was cooled to 25°C, diluted with water (100 mL), and extracted with ethyl acetate (50.0 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1~1 / 1) to obtain tert-butyl(2-(5-((R)-1-(((R)-tert-butylsulfinyl)amino)ethyl)thiophen-2-yl)benzyl)(methyl)carbamate (2.60 g, 5.19 mmol, 80.6% yield, 90.0% purity) as a yellow oil. LCMS[M+1]: 451.4.

[0221] 1 H NMR(400MHz,CDCl3)δ=7.40-7.32(m,2H), 7.31-7.27(m,1H), 7.26-7.22(m,1H), 7.01(s,1H), 6.83(s,1H), 4.95-4.79(m, 1H), 4.67-4.44(m,2H), 3.56(d,J=3.2Hz,1H), 2.93-2.56(m,3H), 1.64(d,J=6.4Hz,3H), 1.56-1.36(m,9H), 1.26(s,9H).

[0222] Step D: To a solution of tert-butyl(2-(5-((R)-1-(((R)-tert-butylsulfinyl)amino)ethyl)thiophen-2-yl)benzyl)(methyl)carbamate (2.60 g, 5.77 mmol, 1.00 equivalent) in THF (20.0 mL) and water (4.00 mL), iodine (439 mg, 1.73 mmol, 349 μL, 0.30 equivalent) was added, and the reaction mixture was stirred at 50°C for 2 hours. The reaction mixture was cooled to 25°C, diluted with saturated sodium bicarbonate (50.0 mL), and extracted with ethyl acetate (20.0 mL x 3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 0 / 1) to obtain (R)-tert-butyl(R)-(2-(5-(1-aminoethyl)thiophen-2-yl)benzyl)(methyl)carbamate (1.50 g, 3.68 mmol, 63.8% yield, 85.0% purity) as a yellow oil. LCMS[2M+1]:693.3.

[0223] 1 H NMR(400MHz,CDCl3)δ=7.39-7.31(m,2H), 7.30-7.20(m,2H), 7.01(d,J=2.8Hz,1H), 6.81(d,J=3. 2Hz,1H), 4.61-4.48(m,3H), 4.04(s,2H), 2.73(s,3H), 1.64(d,J=6.4Hz,3H), 1.57-1.33(m,9H).

[0224] Intermediate K [ka] Step A: To a solution of N-(1-(5-bromothiophen-2-yl)ethyl)-2-methylpropane-2-sulfinamide (0.50 g, 1.61 mmol, 1.00 equivalent) and N,N-dimethyl-1-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanamine (505 mg, 1.93 mmol, 1.20 equivalents) in dioxane (5.00 mL) and water (0.50 mL), cesium carbonate (1.58 g, 4.83 mmol, 3.00 equivalents) and Pd(PPh3)4 (186 mg, 161 μmol, 0.10 equivalents) were added, followed by degassing and purging with nitrogen three times. The reaction mixture was stirred under a nitrogen atmosphere at 110°C for 2 hours. Once complete, the reaction mixture was cooled to 25°C, diluted with water (50.0 mL), and extracted with ethyl acetate (20.0 mL x 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1~0 / 1) to obtain N-(1-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)-2-methylpropane-2-sulfinamide (450 mg, 1.15 mmol, 71.3% yield, 93.0% purity) as a brown oil. LCMS[M+1]: 365.2.

[0225] Step B: To a solution of N-(1-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)-2-methylpropane-2-sulfinamide (410 mg, 1.12 mmol, 1.00 equivalent) in THF (4.00 mL), hydrochloric acid (3.00 M, 375 μL, 1.00 equivalent) was added, and the reaction mixture was stirred at 20°C for 2 hours. After completion, the reaction mixture was diluted with saturated sodium bicarbonate (50.0 mL) and extracted with ethyl acetate (20.0 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to dichloromethane / methanol = 10 / 1) to obtain 1-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethaneamine (200 mg, 691 μmol, 61.5% yield, 90.0% purity) as a yellow oil.

[0226] 1 H NMR(400MHz,DMSO-d6)δ=7.48-7.42(m,1H), 7.41-7.36(m,1H), 7.34-7.28(m,2H), 7.13(d,J=3. 6Hz,1H), 6.96-6.92(m,1H), 4.29-4.21(m,1H), 3.39(s,2H), 2.14(s,6H), 1.38(d,J=6.4Hz,3H).

[0227] Intermediate L [ka] Step A: To a solution of 6-chloroflou[3,4-c]pyridine-1(3H)-one (1.50 g, 8.85 mmol, 1.00 equivalent) in carbon tetrachloride (10.0 mL), AIBN (145 mg, 884 μmol, 0.10 equivalent) and NBS (1.42 g, 7.96 mmol, 0.9 equivalent) were added. The reaction mixture was stirred at 80°C for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 10 / 1) to obtain 3-bromo-6-chloroflou[3,4-c]pyridine-1(3H)-one (1.20 g, 4.83 mmol, 54.6% yield) as a yellow oil. LCMS[M+3]: 249.8.

[0228] 1 H NMR (400MHz, CDCl3) δ=8.84-8.80(m,1H), 7.84(s,1H), 7.47(s,1H).

[0229] Step B: To a solution of 3-bromo-6-chloroflou[3,4-c]pyridine-1(3H)-one (1.20 g, 4.83 mmol, 1.00 equivalent) in ethanol (20.0 mL), hydrazine hydrate (370 mg, 7.24 mmol, 359 μL, 1.50 equivalent) was added at 0°C. The reaction mixture was stirred at 80°C for 30 minutes. The reaction mixture was cooled to 25°C and poured into ice water (1.00 mL) to obtain a suspension. The suspension was filtered, the filter cake was collected, and dried under vacuum to obtain 7-chloropyrido[3,4-d]pyridazin-1-ol (800 mg, 4.41 mmol, 91.2% yield) as a yellow solid. LCMS[M+1]+: 182.0.

[0230] 1 H NMR (400MHz, DMSO-d6) δ = 13.08 (br s, 1H), 9.20 (s, 1H), 8.53 (s, 1H), 8.10 (s, 1H).

[0231] Step C: To a solution of 7-chloropyrido[3,4-d]pyridazine-1-ol (78.0 mg, 430 μmol, 1.00 equivalent) in acetonitrile (2.00 mL), phosphorus(V) oxychloride (231 mg, 1.50 mmol, 139 μL, 3.50 equivalents) was added at 25°C. The reaction mixture was stirred at 80°C for 2 hours. The reaction mixture was cooled to 25°C, poured into saturated sodium bicarbonate aqueous solution (2.00 mL), and stirred at 0°C for 5 minutes. The aqueous phase was extracted with ethyl acetate (3.00 mL × 3). The combined organic phases were washed with brine (2.00 mL × 3), dried on anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain 1,7-dichloropyrido[3,4-d]pyridazine (65.0 mg, crude) as a red solid. LCMS[M+1]: 199.8.

[0232] Intermediate M [ka] Step A: To a mixture of methyl 3,4-dimethoxybenzoate (10.0 g, 51.0 mmol, 1.00 equivalent) in acetic acid (50.0 mL), bromine (8.96 g, 56.1 mmol, 2.89 mL, 1.10 equivalent) in acetic acid (50.0 mL) was added over 1.5 hours at 0°C. Next, the mixture was slowly brought to room temperature and stirred for 45 minutes. Once complete, the reaction was quenched by pouring into water (700 mL), stirred for 30 minutes, then the stirring was stopped, and the mixture was filtered after standing for 1 hour. The collected solid was washed with water (100 mL) and then with aqueous sodium sulfite solution (100 mL). The solid was partially dried and dissolved in hot methanol (300 mL), and the resulting solution was cooled. The cold methanol solution was treated with water (200 mL) to obtain a suspension. The suspension was filtered, the filter cake was collected, and dried under vacuum to obtain methyl 2-bromo-4,5-dimethoxybenzoate (9.00 g, 32.7 mmol, 64.2% yield) as a white powder. LCMS[M+1]:275.3.

[0233] 1H NMR (400MHz, DMSO-d6) δ = 7.36 (s, 1H), 7.24 (s, 1H), 3.84 (s, 3H), 3.82 (s, 3H), 3.79 (s, 3H).

[0234] Step B: The mixture of methyl 2-bromo-4,5-dimethoxybenzoate (6.00 g, 21.8 mmol, 1.00 equivalent), 1-(vinyloxy)butane (10.9 g, 109 mmol, 14.0 mL, 5.00 equivalent), Pd(OAc)2 (490 mg, 2.18 mmol, 0.10 equivalent), triphenylphosphine (1.14 g, 4.36 mmol, 0.20 equivalent), and triethylamine (2.65 g, 26.2 mmol, 3.64 mL, 1.20 equivalent) in acetonitrile (60.0 mL) was degassed, purged three times with nitrogen, and then the reaction mixture was stirred at 100°C under a nitrogen atmosphere for 16 hours. Next, the mixture was cooled to 25°C, filtered, and the filtrate was concentrated under reduced pressure to obtain methylmethyl 2-(1-butoxyvinyl)-4,5-dimethoxybenzoate (6.00 g, crude) as a yellow oil, which was used directly in the next step.

[0235] Step C: A mixture of methyl 2-(1-butoxyvinyl)-4,5-dimethoxybenzoate (6.00 g, 20.4 mmol, 1.00 equivalent) in hydrochloric acid (10% in water, 61.2 g, 168 mmol, 60.0 mL, 8.23) and THF (60.0 mL) was stirred at 20°C for 1 hour. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (50.0 mL x 3). The combined organic layers were adjusted to pH 7 with saturated sodium bicarbonate aqueous solution, then washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was ground in petroleum ether / ethyl acetate = 5 / 1 (50.0 mL) at 20°C for 20 minutes to obtain a suspension. The suspension was filtered, the filter cake was collected, and dried under vacuum to obtain methyl 2-acetyl-4,5-dimethoxybenzoate (3.00 g, 12.6 mmol, 61.8% yield) as a white solid.

[0236] 1H NMR (400MHz, DMSO-d6) δ = 7.26 (s, 1H), 7.17 (s, 1H), 3.86 (s, 3H), 3.84 (s, 3H), 3.77 (s, 3H), 2.46 (s, 3H).

[0237] Step D: To a solution of methyl 2-acetyl-4,5-dimethoxybenzoate (3.00 g, 12.6 mmol, 1.00 equivalent) in ethanol (30.0 mL), hydrazine hydrate (2.22 g, 37.8 mmol, 2.16 mL, 3.00 equivalent) was added at room temperature, and the reaction mixture was stirred at 95 °C for 30 minutes. The reaction mixture was diluted with water (100 mL) and extracted several times with ethyl acetate. The combined organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was pulverized with ethyl acetate (50.0 mL) at 20 °C for 20 minutes to obtain a suspension, filtered, the filter cake was collected, and dried under vacuum to obtain 6,7-dimethoxy-4-methylphthalazine-1(2H)-one (2.00 g, 9.08 mmol, 72.1% yield) as an off-white solid. LCMS[M+1]:221.4.

[0238] 1H NMR (400MHz, DMSO-d6) δ=12.25(s,1H), 7.58(s,1H), 7.21(s,1H), 3.96(s,3H), 3.92(s,3H), 2.48(s,3H).

[0239] Step E: A mixture of 6,7-dimethoxy-4-methylphthalazine-1(2H)-one (1.30 g, 5.90 mmol, 1.00 equivalent) in phosphorus(V) oxychloride (13.0 mL) was stirred at 120°C for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain 1-chloro-6,7-dimethoxy-4-methylphthalazine (1.20 g, crude) as a yellow solid. LCMS[M+1]: 239.0.

[0240] 1H NMR (400MHz, DMSO-d6) δ = 7.80 (s, 1H), 7.64 (s, 1H), 4.13 (s, 3H), 4.12 (s, 3H), 3.08 (s, 3H).

[0241] Intermediate N [ka] Step A: To a solution of 1-(3-(difluoromethyl)-2-methylphenyl)ethane-1-one (0.37 g, 1.99 mmol, 1.00 equivalent) in tetrahydrofuran (10.0 mL), titanium(IV) ethoxide (2.27 g, 9.95 mmol, 2.06 mL, 5.00 equivalent) and (R)-2-methylpropan-2-sulfinamide (724 mg, 5.97 mmol, 3.00 equivalent) were added. The mixture was stirred at 75°C for 16 hours. The reaction mixture was quenched by adding 20.0 mL of saturated sodium bicarbonate aqueous solution at 25°C. The mixture was filtered, and the filtrate was extracted with 45.0 mL (15.0 mL × 3) of ethyl acetate. The combined organic layers were washed with 20.0 mL (20.0 mL × 1) of brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (0-12% ethyl acetate / petroleum ether) to obtain (R,E)-N-(1-(3-(difluoromethyl)-2-methylphenyl)ethylidene)-2-methylpropane-2-sulfinamide (0.36 g, 1.19 mmol, 59.8% yield, 95.0% purity) as a colorless oil.

[0242] 1 H NMR (400MHz, CD3OD) δ=7.55-7.62(m,1H), 7.16-7.51(m,2H), 6.79-7.13(m,1H), 2.48-2.73(m,3H), 2.27-2.47(m,3H), 1.19-1.30(m,9H).

[0243] Step B: To a solution of (R,E)-N-(1-(3-(difluoromethyl)-2-methylphenyl)ethylidene)-2-methylpropane-2-sulfinamide (340 mg, 1.18 mmol, 1.00 equivalent) in tetrahydrofuran (5.00 mL), sodium borohydride (89.5 mg, 2.37 mmol, 2.00 equivalent) was added. The mixture was stirred at 0°C for 1 hour. The reaction mixture was quenched with 10.0 mL of water at 25°C, and then extracted with 30.0 mL of ethyl acetate (10.0 mL x 3). The combined organic layer was washed with brine (10.0 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (0-13% ethyl acetate / petroleum ether) to obtain (R)-N-((R)-1-(3-(difluoromethyl)-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (190 mg, 643 μmol, 54.4% yield, 98.0% purity) as a yellow oil. LCMS[M+1] + = 290.1.

[0244] Step C: The mixture of (R)-N-((R)-1-(3-(difluoromethyl)-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (140 mg, 484 μmol, 1.00 equivalent) in dioxane hydrochloride (4.00 M, 7.00 mL, 57.9 equivalents) was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the crude product (R)-1-(3-(difluoromethyl)-2-methylphenyl)ethane-1-amine (110 mg, 475 μmol, 98.2% yield, 80.0% purity) as a white solid, which was used without further purification. LCMS[M+1] + = 186.0.

[0245] Intermediate O [ka] Step A: To a solution of 3-bromo-2-methylbenzoic acid (100 g, 465 mmol, 1.00 equivalent) and N,O-dimethylhydroxylamine hydrochloride (68.6 g, 512 mmol, 1.10 equivalents, HCl) in DMF (1000 mL), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxidation hexafluorophosphate (195 g, 512 mmol, 1.10 equivalents) and N,N-diisopropylethylamine (180 g, 1.40 mol, 243 mL, 3.00 equivalents) was added. The mixture was stirred at 25°C for 2 hours, then poured into water (1000 mL) and stirred for 15 minutes. The aqueous phase was extracted with ethyl acetate (1000 mL x 3). The combined organic phases were washed with brine (1000 mL x 5), dried on anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain 3,3-bromo-N-methoxy-N,2-dimethylbenzamide (120 g, crude) as a yellow oil. LCMS[M+1]+: 258.0.

[0246] Step B: To a solution of 33-bromo-N-methoxy-N,2-dimethylbenzamide (120 g, 465 mmol, 1.00 equivalent) in THF (100 mL), methylmagnesium bromide (3.0 M, 180 mL, 1.16 equivalent) was added at 0°C. The mixture was stirred at 0-40°C for 3 hours, then cooled to 0°C, hydrochloric acid (6.0 N) (450 mL) was added dropwise, and the mixture was stirred at 40-45°C for 2 hours. The mixture was then cooled to 25°C and poured into saturated ammonium chloride solution (9000 mL). The aqueous phase was extracted with ethyl acetate (1500 mL x 3). The combined organic phases were washed with brine (1000 mL x 3), dried on anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain 1-(3-bromo-2-methylphenyl)ethane-1-one (90.0 g, 422 mmol, 90.9% yield) as a yellow oil.

[0247] 1 H NMR (400MHz, CD3OD) δ=7.70(dd,J=1.2,8.0Hz,1H), 7.62(dd,J=0.8,7.6Hz,1H), 7.19(t,J=8.0Hz,1H), 2.56(s,3H), 2.46(s,3H).

[0248] Step C: To a solution of 1-(3-bromo-2-methylphenyl)ethane-1-one (88.0 g, 413 mmol, 1.00 equivalent) and (S)-2-methylpropan-2-sulfinamide (60.1 g, 496 mmol, 1.20 equivalent) in THF (100 mL), titanium(IV) ethoxide (471 g, 2.07 mol, 428 mL, 5.00 equivalent) and diglym (55.4 g, 413 mmol, 59.1 mL, 1.00 equivalent) was added. The mixture was stirred at 80°C for 2 hours, then poured into water (300 mL) and stirred for 15 minutes. The mixture was filtered, and the filtrate was concentrated under vacuum to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 40 / 1) to obtain (S)-N-(1-(3-bromo-2-methylphenyl)ethylidene)-2-methylpropane-2-sulfinamide (110 g, 348 mmol, 84.2% yield) as a yellow oil.

[0249] 1 H NMR(400MHz,CD3OD)δ=7.63(br t,J=6.8Hz,2H), 7.28(br d,J=7.6Hz,1H), 7.17(t,J=8.0Hz,2H), 7.14-7.02(m,1H), 2.67(s,3H), 2.50(br d,J=4.8Hz,3H), 2.42(s,3H), 2.31(br d,J=17.2Hz,3H), 1.31-1.26(m,9H), 1.24-1.16(m,9H)

[0250] Step D: To a solution of (S)-N-(1-(3-bromo-2-methylphenyl)ethylidene)-2-methylpropane-2-sulfinamide (109 g, 345 mmol, 1.00 equivalent) in THF (1100 mL), L-selectlide (1.0 M, 689 mL, 2.00 equivalent) was added at -78°C. The mixture was stirred at -78°C for 2 hours, then poured into a saturated aqueous solution of ammonium chloride (1000 mL), and stirred at 25°C for 60 minutes. The aqueous phase was extracted with ethyl acetate (1000 mL x 3). The combined organic phases were washed with brine (500 mL x 3), dried on anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1~2 / 1) to obtain the residue. The residue was further washed with petroleum ether to obtain (S)-N-((R)-1-(3-bromo-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (70.0 g, 220 mmol, 63.8% yield) as a white solid. LCMS[M+1]+:318.1.

[0251] Step E: The mixture was stirred at 0°C for 30 minutes in a solution of (S)-N-((R)-1-(3-bromo-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (71.0 g, 223 mmol, 1.00 equivalent) in an HCl / dioxane solution (300 mL) and MeOH (300 mL). The mixture was concentrated under vacuum to obtain (R)-1-(3-bromo-2-methylphenyl)ethane-1-amine (55.0 g, crude, HCl) as a white solid. LCMS[M+1]+: 214.1.

[0252] Step F: (R)-1-(3-bromo-2-methylphenyl)ethane-1-amine (55.0 g, 220 mmol, 1.00 equivalent, HCl) and Boc2O (48.4 g, 222 mmol, 50.9 mL, 1.01 equivalents) were added to dichloromethane (500 mL), to which N,N-diisopropylethylamine (56.7 g, 439 mmol, 76.5 mL, 2.00 equivalents) was added. The mixture was stirred at 0-25°C for 30 minutes, then concentrated under vacuum to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0-100 / 1) to obtain the residue. The residue was further washed with petroleum ether to obtain tert-butyl(R)-(1-(3-bromo-2-methylphenyl)ethyl)carbamate (51.0 g, 162 mmol, 73.9% yield) as a white solid. LCMS[M-55]+:258.0.

[0253] 1 H NMR(400MHz,CD3OD)δ=7.43(d,J=8.0Hz,1H), 7.32(d,J=8.0Hz,1H), 7.10-7.03(m,1H), 4.93(br d,J=6.4Hz,2H), 2.45(s,3H), 1.41(br s,9H), 1.33(d,J=6.8Hz,3H).

[0254] Step G: To a solution of tert-butyl(R)-(1-(3-bromo-2-methylphenyl)ethyl)carbamate (51.0 g, 162 mmol, 1.00 equivalent) in DMF (540 mL), zinc cyanide (22.9 g, 195 mmol, 12.4 mL, 1.20 equivalent) and Pd(PPh3)4 (18.8 g, 16.2 mmol, 0.10 equivalent) were added. The mixture was stirred at 110 °C for 3 hours, then cooled to 25 °C and poured into water (500 mL). The aqueous phase was extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with brine (1000 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 5 / 1) to obtain tert-butyl(R)-(1-(3-cyano-2-methylphenyl)ethyl)carbamate (37.0 g, 142.1 mmol, 87.6% yield) as a white solid. LCMS[M-55]+: 205.0.

[0255] 1 H NMR(400MHz,CD3OD)δ=7.63(d,J=7.6Hz,1H), 7.54(d,J=7.2Hz,1H), 7.39-7.30(m,1H), 4.93(br d,J=6.8Hz,1H), 2.58(s,3H), 1.40(br s,9H), 1.34(d,J=7.2Hz,3H).

[0256] Step H: To a solution of tert-butyl(R)-(1-(3-cyano-2-methylphenyl)ethyl)carbamate (49.0 g, 188 mmol, 1.00 equivalent) in dichloromethane (400 mL), TFA (133 mL) was added. The mixture was stirred at 0°C for 30 minutes, then poured into saturated sodium bicarbonate solution (200 mL), and stirred for another 30 minutes. The aqueous phase was extracted with ethyl acetate (1000 mL x 3). The combined organic phases were washed with brine (200 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain (R)-3-(1-aminoethyl)-2-methylbenzonitrile (26.0 g, 162 mmol, 86.2% yield) as a yellow oil. LCMS[M-16]+: 144.1.

[0257] 1 H NMR(400MHz,DMSO-d6)δ=8.36(br s,2H), 7.86(d,J=8.0Hz,1H), 7.80(dd,J=0.8,7.6Hz,1H), 7.51(t,J=8.0Hz,1H), 4.68(q,J=6.8Hz,1H), 2.55(s,3H), 1.48(d,J=6.8Hz,3H).

[0258] SFC conditions: Column: Chiralpak IC-3 50×4.6mm ID, 3μm; Mobile phase: Phase A for CO2, Phase B for MeOH (0.05% DEA); Gradient elution: MeOH (0.05% DEA) in CO2 from 5% to 40%; Flow rate: 3mL / min; Detector: PDA; Column temperature: 35℃; Back pressure: 100Bar.

[0259] Intermediate P [ka] To a solution of (R)-3-(1-aminoethyl)-2-methylbenzonitrile (16.0 g, 99.9 mmol, 1.00 equivalent) and 1,7-dichloro-4-methylpyrido[3,4-d]pyridazine (21.4 g, 99.9 mmol, 1.00 equivalent) in DMSO (130 mL), cesium fluoride (22.8 g, 150 mmol, 5.52 mL, 1.50 equivalent) was added, and the mixture was stirred at 130 °C for 2 hours. The mixture was then cooled to 25 °C, diluted with water (200 mL), and extracted with ethyl acetate (200 mL x 3). The combined organic phase was washed with brine (100 mL x 3), dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC [column: Kromasil Eternity XT 250×80mm×10um; mobile phase: phase A: water (0.1% TFA), phase B: acetonitrile; B%: 25%~55%]. The combined fractions were combined and the pH was adjusted to pH=8 using an aqueous sodium bicarbonate solution. The suspension was extracted with ethyl acetate (1000 mL × 3), the combined organic phase was washed with brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (R)-3-(1-((7-chloro-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile (14.5 g, 42.9 mmol, 43.0% yield) as a yellow solid.

[0260] 1 H NMR (400MHz, CDCl3) δ=9.19(d,J=0.4Hz,1H), 7.74(s,1H), 7.63(d,J=8.0Hz,1H), 7. 50(dd,J=1.2,7.6Hz,1H), 7.23(t,J=7.6Hz,1H), 5.72(quin,J=6.8Hz,1H), 5.40(br d,J=6.0Hz,1H), 2.86(s,3H), 2.69(s,3H), 1.63(s,3H). Intermediate Q [ka] To a solution of (R)-3-(1-aminoethyl)-2-methylbenzonitrile (5.32 g, 19.4 mmol, 1.00 equivalent, TFA) and 6-bromo-4-chloro-1-methylphthalazine (5.00 g, 19.4 mmol, 1.00 equivalent) in DMSO (30.0 mL), cesium fluoride (5.90 g, 38.8 mmol, 1.43 mL, 2.00 equivalent) and N,N-diisopropylethylamine (5.02 g, 38.8 mmol, 6.76 mL, 2.00 equivalent) were added, and the mixture was stirred at 130°C for 2 hours. The mixture was then cooled to 25°C, diluted with water (10.0 mL), and the aqueous phase was extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with brine (100 mL x 3), dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1~2 / 1) to obtain (R)-3-(1-((7-bromo-4-methylphthalazine-1-yl)amino)ethyl)-2-methylbenzonitrile (5.20 g, 13.6 mmol, 70.2% yield) as a yellow solid. LCMS[M+1]+: 381.1.

[0261] Intermediate R [ka] Step A: A mixture of (R)-2-methylpropan-2-sulfinamide (5.12 g, 42.2 mmol, 1.00 equivalent), 1-(3-bromo-2-methylphenyl)ethane-1-one (9.00 g, 42.2 mmol, 1.00 equivalent), and titanium(IV) isopropoxide (60.0 g, 211 mmol, 62.3 mL, 5.00 equivalent) in THF (90.0 mL) was degassed, purged three times with nitrogen, and stirred at 80°C for 12 hours. The mixture was cooled to 25°C, quenched by adding water (100 mL), filtered, and the filtrate was partitioned into ethyl acetate (300 mL) and water (300 mL). The organic phase was separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0~5 / 1) to obtain (R)-N-(1-(3-bromo-2-methylphenyl)ethylidene)-2-methylpropane-2-sulfinamide (7.23 g, 22.8 mmol, 54.1% yield) as a yellow solid. LCMS[M+3]+: 318.0.

[0262] 1 ¹H NMR (400MHz, CD3OD) δ = 7.67-7.58 (m, 2H), 7.28 (br d, J=7.6Hz, 1H), 7.17 (t, J=8.0Hz, 2H), 7.14-7.01 (m, 1H), 2.67 (s, 3H), 2.50 (br d, J=4.0Hz, 3H), 2.42 (s, 3H), 2.31 (br d, J=17.2Hz, 3H), 1.28 (s, 9H), 1.21 (br d, J=11.2Hz, 9H). (The ratio of E / Z isomers was approximately 1 / 1).

[0263] Step B: To a solution of (R)-N-(1-(3-bromo-2-methylphenyl)ethylidene)-2-methylpropane-2-sulfinamide (400 mg, 1.26 mmol, 1.00 equivalent) in THF (5.00 mL), sodium borohydride (239 mg, 6.32 mmol, 5.00 equivalent) was gradually added at 0°C, and the reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was poured into water (30.0 mL) and stirred for 5 minutes. The resulting aqueous phase was extracted with ethyl acetate (150 mL x 3), the combined organic phase was washed with brine (150 mL x 3), dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to obtain (R)-N-((R)-1-(3-bromo-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (200 mg, 628 μmol, 49.7% yield) as a brown oily substance.

[0264] Step C: To a mixture of (R)-N-((R)-1-(3-bromo-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (250 mg, 786 μmol, 1.00 equivalent), sodium methanesulfinate (176 mg, 1.73 mmol, 2.20 equivalents), potassium carbonate (326 mg, 2.36 mmol, 3.00 equivalents), and L-proline (18.1 mg, 157 μmol, 0.20 equivalents) in dimethyl sulfoxide (3.00 mL), copper(I) iodide (15.0 mg, 78.6 μmol, 0.10 equivalents) was added at 20°C, and the mixture was stirred at 130°C for 3 hours under a nitrogen atmosphere. The mixture was then added to water (15.0 mL), and the mixture was extracted with ethyl acetate (20.0 mL x 3). The combined organic phases were washed with brine (30.0 mL x 3), dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (silica gel plate, petroleum ether / ethyl acetate = 1 / 1) to obtain (R)-2-methyl-N-((R)-1-(2-methyl-3-(methylsulfonyl)phenyl)ethyl)propan-2-sulfinamide (120 mg, 378 μmol, 48.1% yield) as a yellow oil. LCMS[M+1]+: 318.1.

[0265] 1 H NMR(400MHz,DMSO-d6)δ=7.85(dd,J=8.0,1.2Hz,1H), 7.78(d,J=7.6Hz,1H), 7.46(t,J=8.0Hz,1H), 5.42-5.50(m,1H), 4.71-4.80(m,1H), 3.22(s,3H), 2.65(s,3H), 1.46(d,J=6.8Hz,3H), 1.09(s,9H).

[0266] Step D: A mixture of (R)-2-methyl-N-((R)-1-(2-methyl-3-(methylsulfonyl)phenyl)ethyl)propan-2-sulfinamide (120 mg, 378 μmol, 1.00 equivalent) in hydrochloric acid (4.0 M in dioxane, 2.00 mL, 21.2 equivalents) was stirred at 20°C for 1 hour. The mixture was concentrated under reduced pressure to obtain (R)-1-(2-methyl-3-(methylsulfonyl)phenyl)ethane-1-amine (91.0 mg, crude, HCl) as a white solid.

[0267] Intermediate S [ka] Step A: To a solution of methylamine (100 g, 1.48 mol, 3.01 equivalents, HCl salt) in THF (1.00 L), N,N-diisopropylethylamine (237 g, 1.84 mol, 3.73 equivalents), 2-bromo-6-fluorobenzaldehyde (100 g, 493 mmol, 1.00 equivalent), acetic acid (9.00 g, 150 mmol, 0.30 equivalents), and sodium cyanoborohydride (62.0 g, 987 mmol, 2.00 equivalents) were added. The reaction mixture was stirred at 25°C for 3 hours, then diluted with water (500 mL) and extracted with ethyl acetate (1.00 L x 2). The combined organic phases were washed with brine (500 mL), dried over sodium sulfate, filtered, and concentrated under vacuum to obtain 1-(2-bromo-6-fluorophenyl)-N-methylmethaneamine (120 g, 484 mmol, 88% purity) as an off-white solid, which was used directly in the next step. LCMS[M+1]+: 218.0.

[0268] Step B: To a solution of 1-(2-bromo-6-fluorophenyl)-N-methylmethaneamine (120 g, 484 mmol, 88% purity, 1.00 equivalent) in THF (1.00 L), di-tert-butyl dicarbonate (211 g, 968 mmol, 2.00 equivalent) was added, and the mixture was stirred at 25°C for 2 hours. The mixture was filtered, and the filtrate was concentrated under vacuum to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0~100 / 1) to obtain tert-butyl N-[(2-bromo-6-fluorophenyl)methyl]-N-methyl-carbamate (70.0 g, 220 mmol) as a brown oil. LCMS[M-55]+: 261.9

[0269] 1 H NMR (400MHz, DMSO-d6) δ=7.49(d,J=7.6Hz,1H), 7.33-7.26(m,2H), 4.57(s,2H), 2.64(s,3H), 1.38(s,9H).

[0270] Step C: To a solution of tert-butyl(2-bromo-6-fluorobenzyl)(methyl)carbamate (60.0 g, 189 mmol, 1.00 equivalent) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (60.0 g, 236 mmol, 1.25 equivalent) in dioxane (600 mL), Pd(dppf)Cl2CH2Cl2 (15.0 g, 18.4 mmol, 0.10 equivalent) and potassium acetate (72.0 g, 734 mmol, 3.89 equivalent) were added. The reaction mixture was degassed with nitrogen (3 times) and stirred at 100°C for 12 hours under a nitrogen atmosphere. The mixture was cooled to 25°C and concentrated under vacuum to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 100 / 1) to obtain tert-butyl(2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)(methyl)carbamate (80.0 g, 160 mmol, 73% purity) as a yellow oil. LCMS[M-55]+: 266.1.

[0271] Step D: To a solution of tert-butyl(2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)(methyl)carbamate (80.0 g, 160 mmol, 73% purity, 1.00 equivalent) and (R)-N-[(1R)-1-(5-bromo-2-thienyl)ethyl]-2-methyl-propane-2-sulfinamide (56.0 g, 180 mmol, 1.13 equivalents) in dioxane (500 mL) and water (100 mL), cesium carbonate (150 g, 460 mmol, 2.88 equivalents) and Pd(PPh3)4 (20.0 g, 17.3 mmol, 0.10 equivalents) were added under a nitrogen atmosphere, and the mixture was stirred under a nitrogen atmosphere at 100°C for 3 hours. The mixture was diluted with water (500 mL), extracted with ethyl acetate (1.00 L x 2), the organic phase was washed with brine (200 mL), dried over sodium sulfate, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 0 / 1~5 / 1) to obtain tert-butyl(2-(5-((R)-1-(((R)-tert-butylsulfinyl)amino)ethyl)thiophen-2-yl)-6-fluorobenzyl)(methyl)carbamate (84.0 g, 152 mmol, 85% purity) as a yellow oil. LCMS[M-100]+: 369.1.

[0272] 1 H NMR(400MHz,DMSO-d6)δ=7.44-7.36(m,1H), 7.27-7.17(m,2H), 7.08(br d,J=2.8Hz,1H), 6.96(d,J=3.6Hz,1H), 5.88(br d,J=6.8Hz,1H), 4.65(quin,J=6.4Hz,1H), 4.56(s,2H), 2.48(s,3H), 1.55(br d,J=6.8Hz,3H), 1.33(br s,9H), 1.13(s,9H).

[0273] Step E: To a solution of tert-butyl(2-(5-((R)-1-(((R)-tert-butylsulfinyl)amino)ethyl)thiophen-2-yl)-6-fluorobenzyl)(methyl)carbamate (80.0 g, 145 mmol, 85% purity, 1.00 equivalent) in THF (240 mL) and water (48.0 mL), iodine (6.80 g, 26.8 mmol, 0.19 equivalent) was added. The reaction mixture was stirred at 50°C for 2 hours, then diluted with water (500 mL), and extracted with ethyl acetate (500 mL x 2). The organic phase was washed with brine (200 mL), dried over sodium sulfate, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by column chromatography (SiO2, dichloromethane / methanol = 300 / 1 to 10 / 1) to obtain tert-butyl(R)-(2-(5-(1-aminoethyl)thiophen-2-yl)-6-fluorobenzyl)(methyl)carbamate (40.0 g, 110 mmol) as a yellow oil. LCMS[M-16]+: 348.1.

[0274] Intermediate T [ka] Step A: A mixture of 1-(benzyloxy)-3-bromo-5-(trifluoromethyl)benzene (3.00 g, 9.06 mmol, 1.00 equivalent) and Pd(dppf)Cl2 (663 mg, 906 μmol, 0.10 equivalent) in dioxane (50.0 mL) was mixed with tributyl(1-ethoxyvinyl)tin (5.00 g, 13.8 mmol, 4.67 mL, 1.53 equivalent) at 20°C, and the mixture was stirred at 80°C for 12 hours under a nitrogen atmosphere. Next, saturated potassium fluoride solution (100 mL) was added to the mixture, and the solution was stirred at 20°C for 1 hour. The mixture was extracted with ethyl acetate (100 mL x 3), the combined organic phase was washed with brine (100 mL x 3), dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude 1-(benzyloxy)-3-(1-ethoxyvinyl)-5-(trifluoromethyl)benzene (2.90 g, crude) as a yellow oil. This crude oil was used in the next step without further refinement.

[0275] Step B: To a solution of 1-(benzyloxy)-3-(1-ethoxyvinyl)-5-(trifluoromethyl)benzene (2.90 g, 9.00 mmol, crude, 1.00 equivalent) in tetrahydrofuran (30.0 mL), hydrochloric acid (3.0 M in THF, 10.0 mL, 3.33 equivalents) was added, and the solution was stirred at 20°C for 1 hour. Next, the mixture was diluted with water (60.0 mL), extracted with ethyl acetate (20.0 mL x 3), dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 50 / 1 to 10 / 1) to obtain 1-(3-(benzyloxy)-5-(trifluoromethyl)phenyl)ethane-1-one (2.60 g, 8.84 mmol, 98.2% yield) as yellow oil.

[0276] 1 H NMR (400MHz, CDCl3) δ=7.79(s,1H), 7.74(s,1H), 7.45-7.39(m,6H), 5.16(s,2H), 2.63(s,3H).

[0277] Step C: To a solution of 1-(3-(benzyloxy)-5-(trifluoromethyl)phenyl)ethan-1-one (2.60 g, 8.84 mmol, 1.00 equivalent) and (R)-2-methylpropan-2-sulfinamide (1.39 g, 11.5 mmol, 1.30 equivalent) in tetrahydrofuran (40.0 mL), titanium(IV) ethoxide (5.02 g, 17.7 mmol, 5.22 mL, 2.00 equivalent) was added under a nitrogen atmosphere, and the solution was stirred at 70°C for 12 hours. Next, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 20 / 1 to 10 / 1) to obtain (R)-N-(1-(3-(benzyloxy)-5-(trifluoromethyl)phenyl)ethylidene)-2-methylpropane-2-sulfinamide (2.20 g, 5.03 mmol, 57.0% yield) as a yellow oil.

[0278] 1H NMR (400MHz, CDCl3) δ=7.45(d,J=10.0Hz,2H), 7.24-7.13(m,6H), 4.94(s,2H), 2.56(s,3H), 1.10(s,9H).

[0279] Step D: To a mixture of (R)-N-(1-(3-(benzyloxy)-5-(trifluoromethyl)phenyl)ethylidene)-2-methylpropane-2-sulfinamide (2.20 g, 5.54 mmol, 1.00 equivalent) in tetrahydrofuran (30.0 mL), sodium borohydride (270 mg, 7.14 mmol, 1.29 equivalents) was added at 0°C, and the mixture was stirred at 20°C for 3 hours. A saturated aqueous solution of ammonium chloride (80.0 mL) was added to the mixture, and the resulting mixture was stirred at 20°C for 30 minutes. Next, the mixture was extracted with ethyl acetate (80.0 mL x 3), the combined organic phase was washed with brine (80.0 mL x 3), dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 50 / 1 to 3 / 1) to obtain (R)-N-((R)-1-(3-(benzyloxy)-5-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (1.20 g, 3.00 mmol, 54.3% yield) as yellow oil.

[0280] 1 H NMR(400MHz,CDCl3)δ=7.53-7.32(m,5H), 7.23-7.12(m,3H), 5.12(s,2H), 4 .62-4.53(m,1H), 3.43(d,J=2.8Hz,1H), 1.53(d,J=6.4Hz,3H), 1.25(s,9H).

[0281] Step E: To a solution of (R)-N-((R)-1-(3-(benzyloxy)-5-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (1.20 g, 3.00 mmol, 1.00 equivalent), hydrochloric acid (4.0 M in dioxane, 751 μL, 1.00 equivalent) was added, and the solution was stirred at 20°C for 20 minutes. The mixture was concentrated and removed under reduced pressure to obtain (R)-1-(3-(benzyloxy)-5-(trifluoromethyl)phenyl)ethane-1-amine (1.20 g, crude, HCl) as a white solid, which was used without further purification.

[0282] 1 H NMR (400MHz, CDCl3) δ=8.82(s,2H), 7.44-7.31(m,8H), 5.09(s,2H), 4.42(s,1H), 1.43(s,3H).

[0283] Intermediate U [ka] Step A: To a solution of 3-acetyl-5-fluorobenzonitrile (2.00 g, 12.3 mmol, 1.00 equivalent) in tetrahydrofuran (20.0 mL), titanium ethoxide (5.59 g, 24.5 mmol, 5.08 mL, 2.00 equivalent) and (R)-2-methylpropane-2-sulfinamide (1.93 g, 15.9 mmol, 1.30 equivalent) were added. The mixture was degassed, purged three times with nitrogen, and then stirred at 70°C for 12 hours under a nitrogen atmosphere. The mixture was diluted with water (20.0 mL) and filtered. The filtrate was extracted with ethyl acetate (30.0 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1~1 / 1) to obtain (R,E)-N-(1-(3-cyano-5-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide (1.01 g, 3.68 mmol, 30.0% yield, 97.5% purity) as a yellow oil. LCMS[M+1]+: 267.1.

[0284] 1H NMR (400MHz, CDCl3) δ=7.93(s,1H), 7.82-7.79(m,1H), 7.45-7.52(m,1H), 2.79(s,3H), 1.35(s,9H).

[0285] Step B: To a solution of (R,E)-N-(1-(3-cyano-5-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide (900 mg, 3.38 mmol, 1.00 equivalent) in tetrahydrofuran (10.0 mL), sodium borohydride (383 mg, 10.1 mmol, 3.00 equivalent) was added at 0°C. The mixture was heated to 20°C and stirred for 2 hours. The mixture was quenched at 25°C with saturated ammonium chloride aqueous solution (20.0 mL), extracted with ethyl acetate (20.0 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 0 / 1) to obtain (R)-N-((R)1-(3-cyano-5-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (711 mg, 2.52 mmol, 74.5% yield, 95.3% purity) as a yellow oil. LCMS[M+1]+: 269.1.

[0286] 1 H NMR(400MHz, CDCl3)δ=7.46(t,J=1.2Hz,1H), 7.46-7.33(m,1H), 7.31-7.29(m,1 H), 4.60-4.55(m,1H), 3.47(d,J=3.6Hz,1H), 1.54(d,J=6.8Hz,3H), 1.25(s,9H).

[0287] Step C: To a solution of (R)-N-((R)-1-(3-cyano-5-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (711 mg, 2.65 mmol, 1.00 equivalent) in dioxane (3.00 mL), hydrochloric acid (4.0 M, 9.94 mL, 15.0 equivalents) in ethyl acetate was added. The mixture was stirred at 20°C for 2 hours. The mixture was neutralized with saturated sodium bicarbonate solution (10.0 mL), extracted with ethyl acetate (10.0 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (R)-3-(1-aminoethyl)-5-fluorobenzonitrile (330 mg, crude) as a yellow oil.

[0288] 1 H NMR (400MHz, CD3OD) δ=7.72-7.71(m,1H), 7.67-7.66(m,1H), 7.65-7.62(m,1H), 4.59(q,J=6.8Hz,1H), 1.65(d,J=6.8Hz,3H).

[0289] Intermediate V [ka] Step A: 1-Bromo-2-methyl-3-(trifluoromethyl)benzene (10.0 g, 41.8 mmol, 1.00 equivalent) was added to ice-cold concentrated sulfuric acid (100 mL), then potassium nitrate (12.7 g, 125 mmol, 3.00 equivalent) was slowly added at 0°C, and the mixture was stirred at 100°C for 1 hour. Next, the mixture was cooled to 25°C, poured into ice water (500 mL), and extracted with ethyl acetate (300 mL x 3). The combined organic layer was washed with brine (400 mL), dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0~1 / 1) to obtain 1-bromo-2-methyl-5-nitro-3-(trifluoromethyl)benzene (5.20 g, 16.9 mmol, 40.4% yield) as a white oil.

[0290] 1H NMR (400MHz, DMSO-d6) δ=8.72(d,J=2.0Hz,1H), 8.40(d,J=2.4Hz,1H), 2.58-2.62(m,3H).

[0291] Step B: 1-Bromo-2-methyl-5-nitro-3-(trifluoromethyl)benzene (5.20 g, 18.3 mmol, 1.00 equivalent), tributyl(1-ethoxyvinyl)tin (8.60 g, 23.8 mmol, 8.03 mL, 1.30 equivalent), and Pd(PPh3)2Cl2 (385 mg, 549 μmol, 0.03 equivalent) were degassed from dioxane (60.0 mL), purged three times with nitrogen, and the mixture was then stirred under a nitrogen atmosphere at 80°C for 10 hours. The reaction mixture was quenched with saturated potassium fluoride solution (300 mL) and stirred at 25°C for 2 hours. The suspension was extracted with ethyl acetate (180 mL x 3). The combined organic layers were washed with brine (200 mL x 3), dried on sodium sulfate, filtered, and concentrated under reduced pressure to obtain 1-(1-ethoxyvinyl)-2-methyl-5-nitro-3-(trifluoromethyl)benzene (6.00 g, crude) as black oil.

[0292] 1 H NMR(400MHz,CD3OD)δ=8.47(d,J=2.0Hz,1H), 8.32(d,J=2.0Hz,1H), 4.58(d,J=2.8Hz,1H ), 4.32(d,J=2.4Hz,1H), 4.00-3.95(m,2H), 2.56(d,J=1.2Hz,3H), 1.37(t,J=7.0Hz,3H).

[0293] Step C: A mixture of 1-(1-ethoxyvinyl)-2-methyl-5-nitro-3-(trifluoromethyl)benzene (6.00 g, 21.8 mmol, 1.00 equivalent) and hydrochloric acid (3.0 M, 20.7 mL, 2.85 equivalents) in THF (80.0 mL) was stirred at 20°C for 1 hour under a nitrogen atmosphere. Water (100 mL) was added to quench the reaction mixture, and then the mixture was extracted with ethyl acetate (60.0 mL × 3). The combined organic layer was washed with brine (70.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0~10 / 1) to obtain 1-(2-methyl-5-nitro-3-(trifluoromethyl)phenyl)ethane-1-one (4.10 g, 16.5 mmol, 76.0% yield) as a yellow oil.

[0294] 1 H NMR (400MHz, CD3OD) δ=8.67(s,1H), 8.57(s,1H), 2.66(s,3H), 2.60(s,3H).

[0295] Step D: To a solution of 1-(2-methyl-5-nitro-3-(trifluoromethyl)phenyl)ethane-1-one (2.00 g, 8.09 mmol, 1.00 equivalent) and (R)-2-methylpropan-2-sulfinamide (1.27 g, 10.5 mmol, 1.30 equivalent) in THF (20.0 mL), Ti(OEt)4 (3.69 g, 16.1 mmol, 3.36 mL, 2.00 equivalent) was added, and the mixture was stirred at 70°C for 12 hours under a nitrogen atmosphere. The reaction mixture was diluted with water (70.0 mL) and ethyl acetate (60.0 mL), filtered, and the filtrate was extracted with ethyl acetate (50.0 mL x 3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 5 / 1) to obtain (R,E)-2-methyl-N-(1-(2-methyl-5-nitro-3-(trifluoromethyl)phenyl)ethylidene)propan-2-sulfinamide (2.00 g, 5.71 mmol, 70.5% yield) as a yellow oil.

[0296] 1 H NMR (400MHz, CD3OD) δ=8.43(s,1H), 8.30(s,1H), 2.75(s,3H), 2.58(s,3H), 1.30(m,9H).

[0297] Step E: To a solution of (R,E)-2-methyl-N-(1-(2-methyl-5-nitro-3-(trifluoromethyl)phenyl)ethylidene)propan-2-sulfinamide (2.00 g, 5.71 mmol, 1.00 equivalent) in THF (23.0 mL), sodium borohydride (647 mg, 17.1 mmol, 3.00 equivalent) was added at 0°C. The mixture was then stirred at 20°C for 2 hours, saturated sodium bicarbonate was added, and then diluted with water (100 mL). The mixture was extracted with ethyl acetate (60.0 mL x 3), the combined organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0~0 / 1) to obtain (R)-2-methyl-N-((R)-1-(2-methyl-5-nitro-3-(trifluoromethyl)phenyl)ethyl)propan-2-sulfinamide (700 mg, 1.75 mmol, 30.6% yield) as a dark brown oil. LCMS[M+1]+: 353.0.

[0298] 1 H NMR(400MHz,DMSO-d6)δ=8.67(d,J=2.4Hz,1H), 8.31(d,J=2.0Hz,1H), 6.09(d,J =7.2Hz,1H), 4.83-4.79(m,1H), 2.54(s,3H), 1.43(d,J=6.8Hz,1H), 1.11(m,9H).

[0299] Step F: A mixture of (R)-2-methyl-N-((R)-1-(2-methyl-5-nitro-3-(trifluoromethyl)phenyl)ethyl)propan-2-sulfinamide (700 mg, 1.99 mmol, 1.00 equivalent) and iodine (151 mg, 595 μmol, 120 μL, 0.30 equivalent) in tetrahydrofuran (8.00 mL) and water (2.00 mL) was degassed, purged three times with nitrogen, and then the mixture was stirred under a nitrogen atmosphere at 50°C for 2 hours. The reaction was extracted with quenched saturated sodium bicarbonate (50.0 mL) and then with ethyl acetate (30.0 mL × 3). The combined organic phase was washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 0 / 1) to obtain (R)-1-(2-methyl-5-nitro-3-(trifluoromethyl)phenyl)ethane-1-amine (250 mg, 1.01 mmol, 50.7% yield) as a yellow solid.

[0300] 1 H NMR (400MHz, DMSO-d6) δ=8.76(d,J=2.4Hz,1H), 8.30(d,J=2.4Hz,1H), 4.54-4.49(m,1H), 2.57(s,3H), 1.46(d,J=6.4Hz,1H).

[0301] Intermediate W [ka] Step A: To a solution of 1-(3-chloro-2-methylphenyl)ethane-1-one (1.50 g, 8.90 mmol, 1.00 equivalent) in tetrahydrofuran (30.0 mL), titanium ethoxide (6.09 g, 26.7 mmol, 5.53 mL, 3.00 equivalent) and (R)-2-methylpropan-2-sulfinamide (1.40 g, 11.6 mmol, 1.30 equivalent) were added. The mixture was stirred at 70°C for 10 hours. The reaction mixture was quenched at 20°C with sodium bicarbonate (50.0 mL) and then stirred for 10 minutes. The solid was filtered, and the filtrate was extracted with ethyl acetate (20.0 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (R,E)-N-(1-(3-chloro-2-methylphenyl)ethylidene)-2-methylpropane-2-sulfinamide (2.40 g, crude) as a yellow oil. LCMS[M+1]+: 272.0.

[0302] Step B: To a solution of (R,E)-N-(1-(3-chloro-2-methylphenyl)ethylidene)-2-methylpropane-2-sulfinamide (2.30 g, 8.46 mmol, 1.00 equivalent) in tetrahydrofuran (30.0 mL), sodium borohydride (850 mg, 22.5 mmol, 2.66 equivalents) was added at -40°C, and the mixture was stirred at -40°C for 2 hours. The reaction mixture was quenched at 20°C with saturated ammonium chloride solution (50.0 mL), and then stirred for 10 minutes. The solid was filtered off, and the filtration was extracted with ethyl acetate (20.0 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to obtain (R)-N-((R)-1-(3-chloro-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (1.50 g, 5.48 mmol, 64.7% yield) as a colorless oil. LCMS[M+1]+: 274.1.

[0303] Step C: To a solution of (R)-N-((R)-1-(3-chloro-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (1.10 g, 4.02 mmol, 1.00 equivalent) in ethyl acetate (20.0 mL), the hydrochloride salt in ethyl acetate (4.0 M, 30.0 mL) was added at 0°C, and the mixture was stirred at 20°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain (R)-1-(3-chloro-2-methylphenyl)ethane-1-amine (700 mg, crude) as a white solid. LCMS[M+1]+: 170.1.

[0304] Intermediate X [ka] Step A: To a solution of 1-(3-methyl-5-(trifluoromethyl)phenyl)ethane-1-one (500 mg, 2.47 mmol, 1.00 equivalent) and (R)-2-methylpropan-2-sulfinamide (689 mg, 5.69 mmol, 2.30 equivalents) in THF (7.00 mL), Ti(OEt)4 (1.30 g, 5.69 mmol, 1.18 mL, 2.30 equivalents) was added, and the mixture was stirred at 70°C for 12 hours under a nitrogen atmosphere. The reaction mixture was diluted with water (30.0 mL) and ethyl acetate (20.0 mL), filtered, and the filtrate was extracted with ethyl acetate (3 × 20.0 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1) to obtain (R,E)-2-methyl-N-(1-(3-methyl-5-(trifluoromethyl)phenyl)ethylidene)propan-2-sulfinamide (750 mg, 2.46 mmol, 99.3% yield) as a yellow oil. LCMS[M+1]+: 306.1.

[0305] 1 H NMR (400MHz, DMSO-d6) δ=7.99(s,1H), 7.95(s,1H), 7.75(s,1H), 5.75(s,1H), 2.76(s,3H), 2.46(s,3H), 1.22(s,9H).

[0306] Step B: To a solution of (R,E)-2-methyl-N-(1-(3-methyl-5-(trifluoromethyl)phenyl)ethylidene)propan-2-sulfinamide (650 mg, 2.13 mmol, 1.00 equivalent) in THF (15.0 mL), sodium borohydride (253 mg, 6.69 mmol, 3.14 equivalents) was added at -40°C. The mixture was stirred at -40°C for 2 hours. A saturated sodium bicarbonate solution was added to the mixture and diluted with water (50.0 mL). The mixture was extracted with ethyl acetate (3 × 50.0 mL), the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 to 2 / 1) to obtain (R)-2-methyl-N-((R)-1-(3-methyl-5-(trifluoromethyl)phenyl)ethyl)propan-2-sulfinamide (320 mg, 1.04 mmol, 48.9% yield) as a pale yellow solid. LCMS[M+1]+: 308.1.

[0307] 1 H NMR (400MHz, CD3OD) δ=7.52(s,1H), 7.50(s,1H), 7.39(s,1H), 4.56-4.51(m,1H), 2.44(s,1H), 1.54-1.53(d,3H), 1.25(s,9H).

[0308] Step C: A solution of (R)-2-methyl-N-((R)-1-(3-methyl-5-(trifluoromethyl)phenyl)ethyl)propan-2-sulfinamide (305 mg, 992 μmol, 1.00 equivalent) in hydrochloric acid (4.0 M in ethyl acetate, 10.0 mL) was stirred at 25°C for 1 hour and concentrated under reduced pressure to obtain (R)-1-(3-methyl-5-(trifluoromethyl)phenyl)ethane-1-amine (200 mg, crude) as a pale yellow solid. The crude product was used directly in the next step without further purification. LCMS[M+1]+: 204.0.

[0309] Intermediate Y [ka] Step A: To a solution of 1-(4-amino-6-(trifluoromethyl)pyridine-2-yl)ethane-1-one (35.6 g, 175 mmol, 1.00 equivalent) and (R)-2-methylpropan-2-sulfinamide (25.4 g, 209 mmol, 1.20 equivalent) in THF (350 mL), titanium(IV) isopropoxide (149 g, 524 mmol, 155 mL, 3.00 equivalent) and 1,2-dimethoxyethane (15.7 g, 175 mmol, 18.1 mL, 1.00 equivalent) were added. The reaction mixture was stirred at 80°C for 12 hours, and then water (50.0 mL) was added to obtain a suspension. The suspension was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to obtain (R)-N-(1)-(4-amino-6-(trifluoromethyl)pyridine-2-yl)ethylidene)-2-methylpropane-2-sulfinamide (44.0 g, 143 mmol, 82.0% yield) as a brown oil.

[0310] 1 H NMR (400MHz, CDCl3) δ=7.45(d,J=2.0Hz,1H), 6.97(d,J=2.0Hz,1H), 4.56(br s,2H), 2.82(s,3H), 1.33(s,9H).

[0311] Step B: To a solution of (R)-N-(1-(4-amino-6-(trifluoromethyl)pyridine-2-yl)ethylidene)-2-methylpropane-2-sulfinamide (44.0 g, 143 mmol, 1.00 equivalent) in THF (400 mL), sodium borohydride (16.3 g, 430 mmol, 3.00 equivalent) was gradually added at 0°C, and the reaction mixture was stirred at 0°C for 1 hour. The mixture was slowly poured into water (200 mL), stirred for 5 minutes, and then extracted with ethyl acetate (300 mL x 3). The combined organic phases were washed with brine (200 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to obtain (R)-N-((R)-1-(4-amino-6-(trifluoromethyl)pyridine-2-yl)ethyl)-2-methylpropane-2-sulfinamide (24.0 g, 76.2 mmol, 53.2% yield, 98.2% purity) as brown oil.

[0312] 1 H NMR(400MHz,CDCl3)δ=6.63(d,J=2.0Hz,1H), 6.56(d,J=2.0Hz,1H), 5.06(d,J= 6.0Hz,1H), 4.69(s,2H), 4.46-4.39(m,1H), 1.45(d,J=6.8Hz,3H), 1.27(s,9H).

[0313] Step C: (R)-N-((R)-1-(4-amino-6-(trifluoromethyl)pyridine-2-yl)ethyl)-2-methylpropane-2-sulfinamide (23.5 g, 76.0 mmol, 1.00 equivalent) in HCl / dioxane (200 mL) was stirred at 25°C for 2 hours. The mixture was filtered, the filter cake was washed with ethyl acetate (100 mL), and then the filter cake was collected and dried under vacuum to obtain (R)-2-(1-aminoethyl)-6-(trifluoromethyl)pyridine-4-amine (hydrochloride) as a white solid.

[0314] 1H NMR (400MHz, DMSO-d6) δ=8.43(br s,3H), 6.93(br d,J=2.0Hz,2H), 6.74(d,J=1.6Hz,1H), 4.34-4.27(m,1H), 1.45(d,J=6.8Hz,3H).

[0315] Intermediate Z [ka] Step A: To a solution of 1-(2-methylpyridine-3-yl)ethane-1-one (800 mg, 5.92 mmol, 1.00 equivalent) and (S)-2-methylpropan-2-sulfinamide (933 mg, 7.69 mmol, 1.30 equivalents) in tetrahydrofuran (8.00 mL), titanium(IV) ethoxide (2.70 g, 11.8 mmol, 2.45 mL, 2.00 equivalent) and 1,2-dimethoxyethane (533 mg, 5.92 mmol, 615 μL, 1.00 equivalent) were added, and the mixture was stirred at 70°C for 16 hours. After cooling to 25°C, the mixture was concentrated under reduced pressure and purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 to 1 / 1) to obtain (S)-2-methyl-N-(1-)(2-methylpyridine-3-yl)ethylidene)propan-2-sulfinamide (1.25 g, 5.24 mmol, 88.6% yield) as a yellow oil. LCMS[M+1]+: 239.2.

[0316] Step B: To a solution of (S)-2-methyl-N-(1-(2-methylpyridine-3-yl)ethylidene)propan-2-sulfinamide (1.25 g, 5.24 mmol, 1.00 equivalent) in tetrahydrofuran (7.00 mL), L-selectlide (1.0 M in THF, 7.87 mL, 1.50 equivalent) was added dropwise over 30 minutes at -78°C, and the mixture was stirred for a further 1 hour at -78°C. Next, the reaction mixture was quenched by adding saturated ammonium chloride solution (in water, 30.0 mL) at 0°C, and the mixture was stirred for a further 1 hour at 25°C. The solution was then extracted with ethyl acetate (50.0 mL × 3), the combined organic layer was washed with brine (30.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified twice by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 to 0 / 1) to obtain (S)-2-methyl-N-((R)-1-(2-methylpyridine-3-yl)ethyl)propan-2-sulfinamide (600 mg, 2.50 mmol, 47.6% yield) as a white solid. LCMS[M+1]+: 432.3.

[0317] 1 H NMR(400MHz,CDCl3)δ=8.36(dd,J=1.2,3.6Hz,1H), 7.64(dd,J=1.6,8.0Hz,1H), 7.12(dd ,J=4.8,7.6Hz,1H), 4.81-4.70(m,1H), 2.58(s,3H), 1.47(d,J=6.8Hz,3H), 1.14(s,9H).

[0318] SFC conditions: Column: Chiralpak AD-3 50×4.6mm ID, 3um; Mobile phase: Phase A: CO2, and Phase B: MeOH (0.05% diethylamine); Gradient elution: MeOH (0.05% diethylamine) in CO2 from 5% to 40%; Flow rate: 3 mL / min; Detector: PDA; Column temperature: 35°C; Back pressure: 100 Bar.

[0319] Step C: A mixture of (S)-2-methyl-N-((R)-1-(2-methylpyridine-3-yl)ethyl)propan-2-sulfinamide (600 mg, 2.50 mmol, 1.00 equivalent) in HCl·dioxane (3.00 mL) was stirred at 0°C for 30 minutes under a nitrogen atmosphere. A white precipitate formed thereafter, and the suspension was filtered. The cake was collected and dried under vacuum, and the residue was further purified by preparative HPLC [column: Waters Xbridge 150 × 25 mm × 5 μm; mobile phase: phase A: water (0.05% ammonium hydroxide v / v), phase B: MeCN; B%: 3%~33%] to obtain (R)-1-(2-methylpyridine-3-yl)ethane-1-amine (370 mg, 2.23 mmol, 89.2% yield, 82% purity) as a colorless oil. LCMS[M-16]+:120.3.

[0320] Intermediate AA [ka] Step A: To a solution of 1-bromo-3-(difluoromethyl)-2-fluorobenzene (commercially available, 4.50 g, 20.0 mmol, 1.00 equivalent) in 1,4-dioxane (50.0 mL), PdCl2(PPh)3)2 (1.40 g, 2.00 mmol, 0.10 equivalent) and tributyl(1-ethoxyvinyl)tin (21.7 g, 60.0 mmol, 20.3 mL, 3.00 equivalent) were added. The mixture was degassed, purged with nitrogen (3 times), and then stirred at 100°C for 3 hours under a nitrogen atmosphere. The mixture was cooled to room temperature, concentrated under reduced pressure, and potassium fluoride aqueous solution (2.0 M, 100 mL) was added to the residue. The mixture was extracted with ethyl acetate (100 mL x 3), dried on anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain 1-(difluoromethyl)-3-(1-ethoxyvinyl)-2-fluorobenzene (7.50 g, crude) as a brown oil, which was used without further purification.

[0321] Step B: A solution of 1-(difluoromethyl)-3-(1-ethoxyvinyl)-2-fluorobenzene (7.50 g, 34.7 mmol, 1.00 equivalent) in tetrahydrofuran (50.0 mL) was mixed with aqueous hydrochloric acid (30.0 mL, 10% purity) and stirred at 25°C for 1 hour. After this, the pH of the mixture was adjusted from approximately pH to 6-8 with aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate (100 mL x 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 0~5 / 1) to obtain 1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-one (6.01 g, 31.3 mmol, 90.2% yield, 98.0% purity) as a colorless oil. LCMS[M+1]+: 189.1.

[0322] 1 H NMR (400MHz, CDCl3) δ=8.02-7.97(m,1H), 7.80-7.76(m,1H), 7.34(t,J=8.0Hz,1H), 6.94(t,J=14.8Hz,1H), 2.66(d,J=5.2Hz,3H).

[0323] Step C: (S)-2-methylpropan-2-sulfinamide (2.32 g, 19.1 mmol, 1.20 equivalents), 1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-one (3.00 g, 16.0 mmol, 1.00 equivalent), and titanium(IV) ethoxide (7.27 g, 31.9 mmol, 6.60 mL, 2.00 equivalents) were degassed from 2-methyltetrahydrofuran (30.0 mL), purged with nitrogen (3 times), and stirred at 75°C for 4 hours under a nitrogen atmosphere. The reaction mixture was then cooled, diluted with water (50.0 mL), extracted with ethyl acetate (50.0 mL x 3), washed with brine (100 mL x 2), dried on anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 20 / 1~1 / 1) to obtain (S)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide (1.80 g, 6.18 mmol, 38.8% yield). LCMS[M+1]+: 292.2.

[0324] Step D: To a mixture of (S)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide (1.80 g, 6.18 mmol, 1.00 equivalent) in 2-methyltetrahydrofuran (30.0 mL), L-selectlide (3.52 g, 18.5 mmol, 4.10 mL, 3.00 equivalent) was added under a nitrogen atmosphere at -78°C, and the mixture was stirred under a nitrogen atmosphere at -78°C for 3 hours. After this, an additional L-selectlide (1.76 g, 9.30 mmol, 2.00 mL, 1.50 equivalent) was added, the solution was degassed, purged with nitrogen (3 times), and stirred under a nitrogen atmosphere at -78°C for 9 hours. The mixture was cooled to room temperature, diluted with water (30.0 mL), and extracted with ethyl acetate (30.0 mL x 3). The combined organic layers were washed with brine (30.0 mL x 2), dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 20 / 1~1 / 1) to obtain (S)-N-((R)1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (1.30 g, 4.34 mmol, 70.3% yield, 98% purity) as a colorless oil. LCMS[M+1]+: 294.2.

[0325] Step E: To a solution of (S)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (1.29 g, 4.43 mmol, 1.00 equivalent), hydrochloric acid (4.00 M in 1,4-dioxane, 15.0 mL, 14.0 equivalents) was added, and the mixture was stirred at 25°C for 30 minutes. Next, the mixture was diluted with water (30.0 mL), extracted with ethyl acetate (30.0 mL x 3), washed with brine (30.0 mL x 2), dried on anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine (480 mg, 2.13 mmol, 48.0% yield, HCl salt) as a yellow oil, which was used without further purification.

[0326] 1H NMR (400MHz, CDCl3) δ=7.52-7.47(m,2H), 7.24-7.19(m,1H), 6.88(t,J=14.8Hz,1H), 4.85-4.92(m,1H), 1.57(d,J=6.8Hz,3H).

[0327] Step F: A mixture of (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine (300 mg, 1.59 mmol, 1.00 equivalent), 1,7-dichloro-4-methylpyrido[3,4-d]pyridazine (339 mg, 1.59 mmol, 1.00 equivalent), and potassium fluoride (461 mg, 7.93 mmol, 186 μL, 5.00 equivalent) in dimethyl sulfoxide (6.00 mL) was degassed, purged with nitrogen (3 times), and stirred under a nitrogen atmosphere at 130°C for 12 hours. The mixture was then cooled to 25°C, diluted with water (30.0 mL), and extracted with ethyl acetate (30.0 mL x 3). The combined organic layer was washed with brine (30.0 mL x 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) and preparative HPLC [column: Phenomenex luna C18 150×25mm×10um; mobile phase: phase A: water (0.225% formic acid), phase B: acetonitrile; B%: 20% to 50%] to obtain (R)-7-chloro-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-methylpyrido[3,4-d]pyridazine-1-amine (250 mg, 629 μmol, 39.7% yield, 92.3% purity) as a yellow solid. LCMS[M+1]+: 367.2.

[0328] Intermediate AB [ka] Step A: To a solution of 3-bromo-5-fluoro-2-methylbenzoic acid (4.00 g, 17.2 mmol, 1.00 equivalent) and N,O-dimethylhydroxylamine (1.84 g, 18.9 mmol, 1.10 equivalents, HCl salt) in DMF (50.0 mL), N,N-diisopropylethylamine (6.66 g, 51.5 mmol, 8.97 mL, 3.00 equivalent) and HATU (7.83 g, 20.6 mmol, 1.20 equivalent) were added, and the reaction mixture was stirred at 20°C for 2 hours. The reaction mixture was diluted with ethyl acetate (50.0 mL), washed with brine (30.0 mL x 3), and the combined organic phase was collected, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 to 2 / 1) to obtain 3-bromo-5-fluoro-N-methoxy-N,2-dimethylbenzamide (4.70 g, 17.0 mmol, 99.2% yield) as a white solid.

[0329] Step B: To a solution of 3-bromo-5-fluoro-N-methoxy-N,2-dimethylbenzamide (4.70 g, 17.0 mmol, 1.00 equivalent) in THF (100 mL), methylmagnesium bromide (3.0 M, 34.1 mL, 6.00 equivalent) was added dropwise at 0°C. After the addition was complete, the reaction mixture was heated to 45°C and stirred for 5 hours. Next, the mixture was cooled to 25°C, quenched with water (20.0 mL), and extracted with ethyl acetate (50.0 mL × 3). The combined organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1) to obtain 1-(3-bromo-5-fluoro-2-methylphenyl)ethane-1-one (3.80 g, 16.5 mmol, 96.6% yield) as a pale yellow solid.

[0330] 1 H NMR (400MHz, CDCl3) δ=7.43(dd,J=2.8,7.6Hz,1H), 7.19(dd,J=2.8,8.4Hz,1H), 2.55(s,3H), 2.45(d,J=0.4Hz,3H).

[0331] Step C: To a solution of 1-(3-bromo-5-fluoro-2-methylphenyl)ethane-1-one (3.80 g, 16.5 mmol, 1.00 equivalent) and (S)-2-methylpropane-2-sulfinamide (2.79 g, 23.0 mmol, 1.40 equivalent) in THF (60.0 mL), titanium(IV) ethoxide (7.50 g, 32.9 mmol, 6.82 mL, 2.00 equivalent) and 1,2-dimethoxyethane (1.48 g, 16.5 mmol, 1.71 mL, 1.00 equivalent) were added, and the mixture was stirred at 70°C for 12 hours. Next, the reaction mixture was cooled to 25°C and diluted with ethyl acetate (100 mL) and water (10.0 mL) to obtain a suspension. The suspension was filtered, and the filtrate was concentrated under reduced pressure to remove all volatile substances. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 30 / 1 to 20 / 1) to obtain (S)-N-(1-(3-bromo-5-fluoro-2-methylphenyl)ethylidene)-2-methylpropane-2-sulfinamide (4.70 g, 14.1 mmol, 85.5% yield) as a yellow oil. LCMS[M+3]+: 336.0.

[0332] 1 H NMR (400MHz, CDCl3) δ=7.35(br dd,J=2.4,7.6Hz,1H), 6.92(dd,J=2.4,8.4Hz,1H), 2.66(s,3H), 2.37(s,3H), 1.30(s,9H).

[0333] Step D: To a solution of (S)-N-(1-(3-bromo-5-fluoro-2-methylphenyl)ethylidene)-2-methylpropane-2-sulfinamide (5.50 g, 16.5 mmol, 1.00 equivalent) in THF (80.0 mL), L-selectlide (1.0 M, 24.7 mL, 1.50 equivalent) was added dropwise at -78°C, and the reaction mixture was warmed to 0°C and stirred for 2 hours. Next, the mixture was diluted with aqueous ammonium chloride (30.0 mL), and the resulting solution was extracted with ethyl acetate (50.0 mL × 2). The combined organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was ground with petroleum ether (20.0 mL), filtered, and the filter cake was dried under vacuum to obtain (S)-N-((R)-1-(3-bromo-5-fluoro-2-methylphenyl). Ethyl)-2-methylpropane-2-sulfinamide (3.20 g, 9.52 mmol, 57.8% yield) was obtained as a white solid.

[0334] 1 H NMR(400MHz,CDCl3)δ=7.24(dd,J=2.4,7.6Hz,1H), 7.10(dd,J=2.8,10.0Hz,1H), 4.90-4.82(m,1H), 3.30(br d,J=2.8Hz,1H), 2.42(s,3H), 1.48(d,J=6.8Hz,3H), 1.23(s,9H).

[0335] Step E: To a solution of (S)-N-((R)-1-(3-bromo-5-fluoro-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (1.60 g, 4.76 mmol, 1.00 equivalent) in THF (20.0 mL) and water (5.00 mL), iodine (362 mg, 1.43 mmol, 288 μL, 0.30 equivalent) was added, and the mixture was stirred at 50°C for 2 hours. Next, the mixture was cooled to 25°C, and the pH was adjusted to pH=7 with an aqueous sodium bicarbonate solution. The resulting solution was extracted with DCM (20.0 mL × 3), the combined organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain (R)-1-(3-bromo-5-fluoro-2-methylphenyl)ethane-1-amine (1.20 g, crude) as a pale yellow oil. This crude oil was used without further purification.

[0336] Step F: To a solution of (R)-1-(3-bromo-5-fluoro-2-methylphenyl)ethane-1-amine (1.20 g, 5.17 mmol, 1.00 equivalent) in THF (20.0 mL), di-tert-butyl dicarbonate (1.35 g, 6.20 mmol, 1.43 mL, 1.20 equivalent) was added, and the mixture was stirred at 20°C for 3 hours. Next, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 150 / 1 to 70 / 1) to obtain tert-butyl(R)-(1-(3-bromo-5-fluoro-2-methylphenyl)ethyl)carbamate (1.45 g, 4.36 mmol, 84.4% yield) as a white solid.

[0337] Step G: Tert-butyl(R)-(1-(3-bromo-5-fluoro-2-methylphenyl)ethyl) carbamate (1.35 g, 4.06 mmol, 1.00 equivalent), zinc cyanide (954 mg, 8.13 mmol, 516 μL, 2.00 equivalent), DPPF (451 mg, 813 μmol, 0.20 equivalent), zinc powder (26.6 mg, 406 μmol, 0.10 equivalent), and Pd2(dba)3 (372 mg, 406 μmol, 0.10 equivalent) were degassed in dimethylacetamide (20.0 mL), purged with nitrogen (3 times), and the mixture was stirred at 120°C for 6 hours under a nitrogen atmosphere. Next, the mixture was diluted with ethyl acetate (60.0 mL), filtered, the filtrate was washed with brine (30.0 mL x 3), dried on sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 30 / 1) to obtain tert-butyl(R)-(1-(3-cyano-5-fluoro-2-methylphenyl)ethyl)carbamate (1.10 g, 3.95 mmol, 97.3% yield) as a pale yellow solid.

[0338] Step H: To a solution of tert-butyl(R)-(1-(3-cyano-5-fluoro-2-methylphenyl)ethyl)carbamate (1.10 g, 3.95 mmol, 1.00 equivalent) in DCM (5.00 mL), TFA (1.88 g, 16.5 mmol, 1.22 mL, 4.18 equivalents) was added, and the mixture was stirred at 20°C for 1 hour. Next, the mixture was concentrated under reduced pressure, and the residue was adjusted to pH=7 with saturated sodium bicarbonate aqueous solution. The obtained solution was extracted with DCM (50.0 mL), the organic phase was dried over sodium sulfate, and concentrated under vacuum to obtain (R)-3-(1-aminoethyl)-5-fluoro-2-methylbenzonitrile (0.80 g, crude) as a brown oil, which was used without further purification.

[0339] intermediate AC [ka] Step A: To a solution of 2-bromo-4-fluoro-6-(trifluoromethyl)aniline (2.00 g, 7.75 mmol, 1.00 equivalent) and tributyl(1-ethoxyvinyl)tin (2.80 g, 7.75 mmol, 2.62 mL, 1.00 equivalent) in dioxane (20.0 mL), PdCl2(PPh3)2 (544 mg, 775 μmol, 0.10 equivalent) was added under a nitrogen atmosphere, and the mixture was stirred at 80°C for 12 hours. The reaction mixture was then cooled to 25°C, diluted with aqueous potassium fluoride (100 mL), and extracted with ethyl acetate (100 mL x 3). The combined organic layer was washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 2-(1-ethoxyvinyl)-4-fluoro-6-(trifluoromethyl)aniline (4.00 g, crude) as a yellow oil. To a solution of 2-(1-ethoxyvinyl)-4-fluoro-6-(trifluoromethyl)aniline (4.00 g, crude) in tetrahydrofuran (50.0 mL), aqueous hydrochloric acid (4.00 M, 20.0 mL, 1.33 equivalents) was added dropwise. The mixture was then stirred at 25°C for 1 hour, diluted with water (100 mL), and extracted with ethyl acetate (300 mL x 3). The combined organic layer was washed with brine (200 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 30 / 1 to 3 / 1) to obtain compound 1-(2-amino-5-fluoro-3-(trifluoromethyl)phenyl)ethane-1-one (5.60 g, 25.3 mmol, 42.0% yield, 99.9% purity) as a yellow solid.

[0340] 1 H NMR (400MHz, DMSO-d6) δ=7.99(d,J=9.2Hz,1H), 7.65-7.61(m,1H), 7.33(s,2H), 2.59(s,3H).

[0341] Step B: To a solution of 1-(2-amino-5-fluoro-3-(trifluoromethyl)phenyl)ethane-1-one (5.60 g, 25.3 mmol, 1.00 equivalent) in hydrochloric acid (50.0 mL) and water (100 mL), sodium nitrite (2.27 g, 32.9 mmol, 1.30 equivalent) was gradually added, and then potassium iodide (8.41 g, 50.6 mmol, 2.00 equivalent) was added to the mixture at 0°C. After the addition was complete, the reaction mixture was stirred at 25°C for 12 hours, then diluted with water (100 mL), and extracted with ethyl acetate (200 mL x 3). The combined organic layer was washed with sodium sulfate (200 mL x 3), dried on sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 50 / 1 to 10 / 1) to obtain compound 1-(5-fluoro-2-iodo-3-(trifluoromethyl)phenyl)ethane-1-one (5.60 g, 10.3 mmol, 40.8% yield, 61.2% purity) as a yellow solid.

[0342] 1 H NMR (400MHz, DMSO-d6) δ = 7.83-7.76 (m, 1H), 7.74-7.71 (m, 1H), 2.56 (s, 3H).

[0343] Step C: To a solution of methylboronic acid (1.62 g, 27.1 mmol, 2.50 equivalents) and 1-(5-fluoro-2-iodo-3-(trifluoromethyl)phenyl)ethane-1-one (3.60 g, 10.8 mmol, 1.00 equivalent) in dioxane (20.0 mL), Pd(dppf)Cl2 (400 mg, 542 μmol, 0.05 equivalents) and potassium carbonate (7.49 g, 54.2 mmol, 5.00 equivalents) were added under a nitrogen atmosphere, and the mixture was stirred at 90°C for 12 hours. Next, the mixture was cooled to 25°C, diluted with water (50.0 mL), and extracted with ethyl acetate (100 mL x 3). The combined organic layer was washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 50 / 1 to 10 / 1) to obtain compound 1-(5-fluoro-2-methyl-3-(trifluoromethyl)phenyl)ethane-1-one (1.70 g, 7.72 mmol, 71.2% yield) as a yellow oil.

[0344] 1 H NMR (400MHz, CDCl3) δ=7.47(dd,J=2.8,8.8Hz,1H), 7.36-7.30(m,1H), 2.58(s,3H), 2.47(s,3H).

[0345] Step D: To a solution of 1-(5-fluoro-2-methyl-3-(trifluoromethyl)phenyl)ethane-1-one (2.20 g, 9.99 mmol, 1.00 equivalent) and (R)-2-methylpropan-2-sulfinamide (2.42 g, 20.0 mmol, 2.00 equivalent) in tetrahydrofuran (15.0 mL), titanium(IV) isopropoxide (5.68 g, 20.0 mmol, 5.90 mL, 2.00 equivalent) and 1-methoxy-2-(2-methoxyethoxy)ethane (4.12 g, 30.7 mmol, 4.40 mL, 3.08 equivalent) were added, and the mixture was stirred at 75°C for 12 hours. Next, the mixture was cooled to 25°C and diluted with water (50.0 mL) to obtain a suspension. The obtained suspension was filtered, and the filtrate was diluted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (50.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to obtain compound (R)-N-(1-(5-fluoro-2-methyl-3-(trifluoromethyl)phenyl)ethylidene)-2-methylpropane-2-sulfinamide (1.50 g, 4.64 mmol, 46.4% yield) as a yellow oil.

[0346] 1 H NMR (400MHz, CDCl3) δ=7.39(dd,J=2.2,8.8Hz,1H), 7.10(dd,J=2.4,8.4Hz,1H), 2.68(s,3H), 2.41(s,3H), 1.30(s,9H).

[0347] Step E: To a solution of (R)-N-(1-(5-fluoro-2-methyl-3-(trifluoromethyl)phenyl)ethylidene)-2-methylpropane-2-sulfinamide (1.90 g, 5.88 mmol, 1.00 equivalent) in tetrahydrofuran (20.0 mL), sodium borohydride (667 mg, 17.6 mmol, 3.00 equivalent) was gradually added at 0°C. The reaction mixture was stirred at 0°C for 2 hours, then slowly diluted with saturated ammonium chloride aqueous solution (50.0 mL) and stirred for 30 minutes. The resulting mixture was extracted with ethyl acetate (100 mL x 3), the combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to obtain (R)-N-((R)-1-(5-fluoro-2-methyl-3-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (1.30 g, 4.00 mmol, 68.0% yield) as a yellow oil.

[0348] 1 H NMR (400MHz, CDCl3) δ=7.40-7.28(m,2H), 4.95-4.84(m,1H), 3.40-3.32(m,1H), 2.43(s,3H), 1.49(d,J=6.4Hz,3H), 1.23(s,9H).

[0349] Step F: To a solution of (R)-N-((R)-1-(5-fluoro-2-methyl-3-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (1.30 g, 4.00 mmol, 1.00 equivalent) in dichloromethane (5.00 mL, 5.00 equivalent), hydrochloric acid (4.00 M in 1,4-dioxane, 5.00 mL, 5.0 equivalent) was added, and the mixture was stirred at 25°C for 1 hour. Next, the mixture was concentrated under reduced pressure to obtain compound (R)-1-(5-fluoro-2-methyl-3-(trifluoromethyl)phenyl)ethane-1-amine (700 mg, 2.81 mmol, 70.4% yield, 88.9% purity, HCl salt) as a yellow oil, which was used directly without further purification.

[0350] Intermediate AD [ka] Step A: To a solution of 3-bromo-2,5-difluorobenzaldehyde (4.00 g, 18.1 mmol, 1.00 equivalent) and (R)-2-methylpropane-2-sulfinamide (3.07 g, 25.3 mmol, 1.40 equivalent) in THF (50.0 mL), titanium(IV) ethoxide (8.26 g, 36.2 mmol, 7.51 mL, 2.00 equivalent) and 1,2-dimethoxyethane (1.63 g, 18.1 mmol, 1.88 mL, 1.00 equivalent) were added, and the mixture was stirred at 70°C for 12 hours. Next, the mixture was cooled to 25°C and slowly diluted with ethyl acetate (50.0 mL) and water (5.00 mL) to obtain a suspension. The suspension was filtered, the filtrate was concentrated under reduced pressure, and then purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 10 / 1) to obtain (S)-N-(3-bromo-2,5-difluorobenzylidene)-2-methylpropane-2-sulfinamide (5.70 g, 17.6 mmol, 97.1% yield) as a white solid.

[0351] 1 H NMR (400MHz, CDCl3) δ=8.81(d,J=2.4Hz,1H), 7.74(dd,J=6.0,8.4Hz,1H), 7.44(dd,J=5.2,8.8Hz,1H), 1.28(s,9H).

[0352] Step B: To a solution of (S)-N-(3-bromo-2,5-difluorobenzylidene)-2-methylpropane-2-sulfinamide (5.50 g, 17.0 mmol, 1.00 equivalent) in DCM (60.0 mL), methylmagnesium bromide (3.0 M, 17.0 mL, 3.00 equivalent) was added dropwise at -60°C, and the mixture was then warmed to 0°C and stirred for 1 hour. The mixture was diluted with aqueous ammonium chloride (50.0 mL), and the resulting aqueous solution was extracted with ethyl acetate (50.0 mL x 3). The combined organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 to 2 / 1) to obtain ((S)-N-((R)-1-(3-bromo-2,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (3.50 g, 10.3 mmol, 60.6% yield) as a white solid.

[0353] 1 H NMR(400MHz,CDCl3)δ=7.31-7.26(m,1H), 7.16(dd,J=6.4,8.8Hz,1H), 4.89-4.78(m,1H), 3.35(br d,J=4.0Hz,1H), 1.56(d,J=6.8Hz,3H), 1.23(s,9H).

[0354] Step C: To a solution of (S)-N-((R)-1-(3-bromo-2,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (1.50 g, 4.41 mmol, 1.00 equivalent) in THF (20.0 mL) and water (5.00 mL), iodine (336 mg, 1.32 mmol, 266 μL, 0.30 equivalent) was added, and the mixture was stirred at 50°C for 2 hours. Next, the mixture was cooled to 25°C, and the pH was adjusted to pH=7 with an aqueous sodium bicarbonate solution. The resulting aqueous solution was extracted with DCM (20.0 mL × 3), the combined organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain (R)-1-(3-bromo-2,5-difluorophenyl)ethane-1-amine (1.20 g, crude) as a pale yellow oil. This crude oil was used directly without further purification.

[0355] Step D: To a solution of (R)-1-(3-bromo-2,5-difluorophenyl)ethane-1-amine (1.20 g, 5.08 mmol, 1.00 equivalent) in THF (20.0 mL), di-tert-butyl dicarbonate (1.22 g, 5.59 mmol, 1.28 mL, 1.10 equivalent) was added, and the mixture was stirred at 20°C for 2 hours. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 150 / 1 to 80 / 1) to obtain tert-butyl(R)-(1-(3-bromo-2,5-difluorophenyl)ethyl)carbamate (1.30 g, 3.87 mmol, 76.1% yield) as a white solid.

[0356] Step E: A mixture of tert-butyl(R)-(1-(3-bromo-2,5-difluorophenyl)ethyl) carbamate (1.20 g, 3.57 mmol, 1.00 equivalent), zinc cyanide (838 mg, 7.14 mmol, 453 μL, 2.00 equivalent), zinc (23.3 mg, 357 μmol, 0.10 equivalent), DPPF (396 mg, 714 μmol, 0.20 equivalent), and Pd2(dba)3 (327 mg, 357 μmol, 0.10 equivalent) in dimethylacetamide (20.0 mL) was degassed, purged with nitrogen (3 times), and the mixture was stirred under a nitrogen atmosphere at 115°C for 3 hours. Next, the mixture was cooled to 25°C, diluted with ethyl acetate (100 mL), the organic phase was washed with brine (50.0 mL x 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 30 / 1) to obtain tert-butyl(R)-(1-(3-cyano-2,5-difluorophenyl)ethyl)carbamate (0.90 g, 3.19 mmol, 89.3% yield) as a pale yellow solid.

[0357] Step F: To a solution of tert-butyl(R)-(1-(3-cyano-2,5-difluorophenyl)ethyl)carbamate (0.90 g, 3.19 mmol, 1.00 equivalent) in DCM (10.0 mL), TFA (4.62 g, 40.5 mmol, 3.00 mL, 12.7 equivalents) was added, and the reaction mixture was stirred at 20°C for 1 hour. Next, the reaction mixture was concentrated under reduced pressure, and the residue was diluted with water (10.0 mL). The pH of the solution was adjusted to pH=7 with aqueous sodium bicarbonate, and the resulting aqueous solution was extracted with DCM (20.0 mL × 2). The combined organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain (R)-3-(1-aminoethyl)-2,5-difluorobenzonitrile (700 mg, crude) as a pale yellow oil. This compound was used directly without further purification.

[0358] Intermediate AE [ka] Step A: To a solution of 1-bromo-3-fluoro-2-(trifluoromethyl)benzene (39.0 g, 160 mmol, 1.00 equivalent) in dimethyl sulfoxide (200 mL), zinc cyanide (11.5 g, 176 mmol, 7.56 mL, 1.10 equivalent) was added, and the reaction mixture was stirred at 80°C for 16 hours. Next, the mixture was cooled to 25°C, diluted with ethyl acetate (1.00 L), the organic phase was separated, washed with water (500 mL x 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1 / 0 to 2 / 1) to obtain 3-bromo-2-(trifluoromethyl)benzonitrile (29.0 g, 116 mmol, 72.3% yield) as a white solid.

[0359] 1 H NMR (400MHz, DMSO-d6) δ = 8.20 (d, J = 8.0 Hz, 1H), 8.10 (d, J = 7.6 Hz, 1H), 7.75 (t, J = 8.0 Hz, 1H).

[0360] Step B: To a solution of 3-bromo-2-(trifluoromethyl)benzonitrile (29.0 g, 116 mmol, 1.00 equivalent) and tributyl(1-ethoxyvinyl)tin (50.3 g, 139 mmol, 47.0 mL, 1.20 equivalent) in toluene (250 mL), Pd(PPh3)4 (6.70 g, 5.80 mmol, 0.05 equivalent) was added under a nitrogen atmosphere, and the mixture was stirred at 100°C for 16 hours. The reaction mixture was cooled to 25°C, diluted with water (500 mL) and ethyl acetate (200 mL), and finally potassium fluoride (50.0 g) solid was added. The mixture was stirred at 25°C for 30 minutes, then the organic layer was separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1~5 / 1) to obtain the crude product. The crude product was pulverized with petroleum ether (50.0 mL), filtered, and the filtrate was concentrated under reduced pressure to obtain 3-(1-ethoxyvinyl)-2-(trifluoromethyl)benzonitrile (8.00 g, 33.2 mmol, 23.0% yield) as a pale yellow oil.

[0361] 1 H NMR(400MHz,CDCl3)δ=7.82(d,J=7.2Hz,1H), 7.70(d,J=7.2Hz,1H), 7.65-7.59(t,J=7.6Hz,1 H), 4.37(d,J=2.8Hz,1H), 4.25(d,J=2.8Hz,1H), 3.90(q,J=7.2Hz,2H), 1.36(t,J=6.8Hz,3H).

[0362] Step C: To a solution of 3-(1-ethoxyvinyl)-2-(trifluoromethyl)benzonitrile (7.00 g, 29.0 mmol, 1.00 equivalent) in tetrahydrofuran (10.0 mL), hydrochloric acid (2.00 M, 29.0 mL, 2.00 equivalent) was added, and the reaction mixture was stirred at 20°C for 2 hours. Next, the pH of the mixture was adjusted to pH=8 with aqueous sodium bicarbonate solution, and then diluted with water (100 mL). The resulting solution was extracted with ethyl acetate (50.0 mL × 3), the combined organic phase was washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1~5 / 1) to obtain 3-acetyl-2-(trifluoromethyl)benzonitrile (5.30 g, 24.8 mmol, 85.6% yield) as a colorless oil.

[0363] 1 H NMR (400MHz, DMSO-d6) δ = 8.25 (dd, J = 0.8, 7.6Hz, 1H), 8.07-7.94 (m, 2H), 2.60 (s, 3H).

[0364] Step D: To a solution of 3-acetyl-2-(trifluoromethyl)benzonitrile (1.00 g, 4.69 mmol, 1.00 equivalent) and (R)-2-methylpropane-2-sulfinamide (625 mg, 5.16 mmol, 1.10 equivalents) in tetrahydrofuran (2.00 mL), 1,2-dimethoxyethane (423 mg, 4.69 mmol, 488 μL, 1.00 equivalent) and titanium(IV) ethoxide (3.21 g, 14.1 mmol, 2.92 mL, 3.00 equivalent) were added, and the reaction mixture was stirred at 80°C for 16 hours. The mixture was concentrated under reduced pressure, the residue was diluted with ethyl acetate (100 mL), and poured into a mixture of ceratom (20.0 g) and saturated sodium bicarbonate (10.0 g) in water (100 mL). The mixture was stirred, then filtered, and the filter cake was stirred with ethyl acetate (30.0 mL) and filtered again. This procedure was repeated three times until the product cake was washed away. The combined filtrate was separated, and the aqueous phase was extracted with ethyl acetate (100 mL). The combined organic layer was washed with brine (50.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ethyl acetate / petroleum ether, 0-30%) to obtain (R)-N-(1-(3-cyano-2-(trifluoromethyl)phenyl)ethylidene)-2-methylpropane-2-sulfinamide (950 mg, 2.99 mmol, 63.7% yield, 99.5% purity) as a pale yellow oil. LCMS[M+1]+: 317.1.

[0365] 1 H NMR (400MHz, CDCl3) δ=7.92-7.80(m,1H), 7.77-7.65(m,1H), 7.61-7.37(m,1H), 2.74-2.38(m,3H), 1.29-1.24(m,9H).

[0366] Step E: To a solution of (R)-N-(1-(3-cyano-2-(trifluoromethyl)phenyl)ethylidene)-2-methylpropane-2-sulfinamide (1.70 g, 5.37 mmol, 1.00 equivalent) in tetrahydrofuran (20.0 mL), sodium borohydride (610 mg, 16.0 mmol, 3.00 equivalent) was gradually added at 0°C under a nitrogen atmosphere. After addition, the mixture was stirred at this temperature for 30 minutes, then warmed to 25°C and stirred for a further 3 hours. Next, the mixture was diluted dropwise with saturated ammonium chloride aqueous solution (100 mL) under a nitrogen atmosphere while stirring at 25°C, and then extracted with ethyl acetate (150 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 to 1 / 1) to obtain (R)-N-(1-(3-cyano-2-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (1.50 g, 4.71 mmol, 87.7% yield, mixture of diastereomers) as a white solid. LCMS[M+1]+: 319.1.

[0367] Step F: A mixture of (R)-N-(1-(3-cyano-2-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (1.4 g, 4.40 mmol, 1.00 equivalent) in HCl-dioxane (10.0 mL) was stirred at 5°C for 30 minutes. After this, a white precipitate formed, and the suspension was filtered. The filter cake was collected and dried under vacuum to obtain 3-(1-aminoethyl)-2-(trifluoromethyl)benzonitrile (850 mg, 3.39 mmol, 77.1% yield, HCl salt) as a white solid. LCMS[M+1]+: 215.1.

[0368] 1 H NMR(400MHz,DMSO-d6)δ=8.84(s,3H), 8.38(br d,J=8.0Hz,1H), 8.19(d,J=7.6Hz,1H), 8.12-7.95(m,1H), 4.64(br d,J=6.0Hz,1H), 1.56(d,J=6.4Hz,3H).

[0369] Step G: A mixture of 3-(1-aminoethyl)-2-(trifluoromethyl)benzonitrile (300 mg, 1.40 mmol, 1.00 equivalent, HCl salt), 1,7-dichloro-4-methylpyrido[3,4-d]pyridazine (300 mg, 1.40 mmol, 1.00 equivalent), diisopropylethylamine (499 mg, 3.86 mmol, 673 μL, 2.76 equivalents), and cesium fluoride (400 mg, 2.63 mmol, 97.0 μL, 1.88 equivalents) in dimethyl sulfoxide (1.50 mL) was degassed, purged with nitrogen (3 times), and the mixture was stirred under a nitrogen atmosphere at 130°C for 1 hour. The mixture was then cooled to 25°C, ethyl acetate (60.0 mL) was added, the organic solution was washed with brine (30.0 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 to 1 / 1) to obtain 3-(1-((7-chloro-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-(trifluoromethyl)benzonitrile (160 mg, 408 μmol, 29.2% yield) as a white solid. LCMS[M+1]+: 392.1.

[0370] 3-(1-((7-chloro-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-(trifluoromethyl)benzonitrile (160 mg) was further purified using SFC [column: DAIEL CHIRALPAK AD (250 mm × 30 mm, 10 μm); mobile phase: phase A: in MeOH (0.1% NH4OH), phase B: CO2; B%: 20%~20%] to obtain the first eluted isomer as a white solid (R)-3-(1-((7-chloro-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-(trifluoromethyl)benzonitrile (62.0 mg, 158 μmol, 39.0% yield). LCMS[M+1]+: 392.1.

[0371] 1H NMR(400MHz,CD3OD)δ=9.24(d,J=0.8Hz,1H), 8.46(d,J=0.8Hz,1H), 8.05(d,J=8.4Hz,1H), 7.80 (d,J=7.2Hz,1H), 7.71-7.57(m,1H), 5.74(q,J=6.8Hz,1H), 2.74(s,3H), 1.68(d,J=6.8Hz,3H).

[0372] Intermediate AF [ka] Step A: To a solution of 4-fluoro-3-nitro-5-(trifluoromethyl)benzoic acid (2.00 g, 7.90 mmol, 1.00 equivalent) in tetrahydrofuran (15.0 mL), palladium carbon (7.90 mmol, 10% purity, 1.00 equivalent) was added under a nitrogen atmosphere, and the mixture was stirred under a hydrogen atmosphere (15 Psi) at 25°C for 2 hours. Next, the mixture was filtered and concentrated under reduced pressure to obtain compound 3-amino-4-fluoro-5-(trifluoromethyl)benzoic acid (1.60 g, 7.17 mmol, 90.8% yield) as a white solid.

[0373] 1 H NMR (400MHz, DMSO-d6) δ = 7.68-7.64 (m, 1H), 7.32-7.29 (m, 1H), 5.95-5.89 (m, 2H).

[0374] Step B: To a solution of 3-amino-4-fluoro-5-(trifluoromethyl)benzoic acid (1.50 g, 6.72 mmol, 1.00 equivalent) and N,O-dimethylhydroxylamine (830 mg, 13.45 mmol, 2.00 equivalent) in N,N-dimethylformamide (10.0 mL), HATU (5.11 g, 13.5 mmol, 2.00 equivalent) and N,N-diisopropylethylamine (2.61 g, 20.2 mmol, 3.50 mL, 3.00 equivalent) were added, and the mixture was stirred at 25°C for 12 hours. The mixture was diluted with water (50.0 mL) and then extracted with ethyl acetate (50.0 mL x 3). The combined organic layer was washed with brine (50.0 mL x 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to obtain compound 3-amino-4-fluoro-N-methoxy-N-methyl-5-(trifluoromethyl)benzamide (1.50 g, 5.64 mmol, 83.9% yield) as a yellow oil.

[0375] 1 H NMR(400MHz,CDCl3)δ=7.38-7.34(m,2H), 3.57(s,3H), 3.36(s,3H)

[0376] Step C: To a solution of 3-amino-4-fluoro-N-methoxy-N-methyl-5-(trifluoromethyl)benzamide (1.50 g, 5.64 mmol, 1.00 equivalent) in dichloromethane (10.0 mL), di-tert-butyl dicarbonate (3.69 g, 16.9 mmol, 3.88 mL, 3.00 equivalent) and 4-dimethylaminopyridine (688 mg, 5.64 mmol, 1.00 equivalent) were added, and the mixture was stirred at 25°C for 12 hours. The reaction mixture was diluted with water (50.0 mL) and then extracted with ethyl acetate (50.0 mL x 3). The combined organic layers were washed with brine (50.0 mL x 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to obtain the compound tert-butyl(tert-butoxycarbonyl)(2-fluoro-5-(methoxy(methyl)carbamoyl)-3-(trifluoromethyl)phenyl)carbamate (2.00 g, 4.29 mmol, 76.1% yield) as a yellow oil.

[0377] 1 H NMR (400MHz, CDCl3) δ=8.05-8.01(m,1H), 7.87-7.84(m,1H), 3.55(s,3H), 3.39(s,3H), 1.42(s,18H).

[0378] Step D: To a solution of tert-butyl(tert-butoxycarbonyl)(2-fluoro-5-(methoxy(methyl)carbamoyl)-3-(trifluoromethyl)phenyl)carbamate (1.80 g, 3.86 mmol, 1.00 equivalent) in tetrahydrofuran (20.0 mL), methylmagnesium bromide solution (3.00 M, 3.86 mL, 3.00 equivalent) was added at 0°C, and the mixture was stirred at 0°C for 12 hours. Next, the reaction mixture was diluted with water (100 mL), and the solution was extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (100 mL x 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to obtain the compound tert-butyl(5-acetyl-2-fluoro-3-(trifluoromethyl)phenyl)carbamate (1.10 g, 3.42 mmol, 88.7% yield) as a yellow oil.

[0379] 1 H NMR (400MHz, CDCl3) δ=8.98(d,J=6.4Hz,1H), 7.90-7.87(m,1H), 6.86(s,1H), 2.65(s,3H), 1.56(s,9H).

[0380] Step E: To a solution of tert-butyl(5-acetyl-2-fluoro-3-(trifluoromethyl)phenyl) carbamate (1.10 g, 2.61 mmol, 1.00 equivalent) and (R)-2-methylpropane-2-sulfinamide (950 mg, 7.83 mmol, 3.00 equivalent) in tetrahydrofuran (10.0 mL), titanium(IV) isopropoxide (1.48 g, 5.22 mmol, 1.54 mL, 2.00 equivalent) and 1-methoxy-2-(2-methoxyethoxy)ethane (1.87 g, 13.97 mmol, 2.00 mL, 5.35 equivalent) were added, and the mixture was stirred at 70°C for 12 hours. Next, the mixture was diluted with water (50.0 mL) and extracted with ethyl acetate (50.0 mL x 3). The combined organic layers were washed with brine (50.0 mL x 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to obtain the compound tert-butyl(R)-(5-(1-((tert-butylsulfinyl)imino)ethyl)-2-fluoro-3-(trifluoromethyl)phenyl)carbamate (1.00 g, 2.36 mmol, 90.1% yield) as a yellow oil.

[0381] 1 H NMR (400MHz, CDCl3) δ=8.86(d,J=6.4Hz,1H), 7.82(d,J=6.0Hz,1H), 6.85(s,1H), 2.79(s,3H), 1.54(s,9H), 1.33(s,9H).

[0382] Step F: To a solution of tert-butyl(R)-(5-(1-((tert-butylsulfinyl)imino)ethyl)-2-fluoro-3-(trifluoromethyl)phenyl)carbamate (1.00 g, 2.36 mmol, 1.00 equivalent) in tetrahydrofuran (10.0 mL), sodium borohydride (268 mg, 7.07 mmol, 3.00 equivalent) was added at 0°C, and the mixture was stirred at 0°C for 2 hours. Next, the mixture was diluted with water (50.0 mL) and extracted with ethyl acetate (50.0 mL x 3). The combined organic layer was washed with brine (50.0 mL x 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to obtain the compound tert-butyl(5-((R)-1-(((R)-tert-butylsulfinyl)amino)ethyl)-2-fluoro-3-(trifluoromethyl)phenyl)carbamate (620 mg, 1.45 mmol, 61.7% yield) as a white solid.

[0383] 1 H NMR (400MHz, CDCl3) δ=8.34(d,J=6.4Hz,1H), 7.23-7.20(m,1H), 6.80(s,1H), 4.56-5.53(m,1H), 1.54-1.52(m,12H), 1.24(s,9H).

[0384] Step G: To a solution of tert-butyl(5-((R)-1-(((R)-tert-butylsulfinyl)amino)ethyl)-2-fluoro-3-(trifluoromethyl)phenyl)carbamate (620 mg, 1.45 mmol, 1.00 equivalent) in dichloromethane (5.00 mL), the hydrochloride salt (4.00 M in 1,4-dioxane, 5.00 mL, 13.76 equivalents) was added, and the mixture was stirred at 25°C for 1 hour. Next, the mixture was concentrated under reduced pressure to obtain compound (R)-5-(1-aminoethyl)-2-fluoro-3-(trifluoromethyl)aniline (280 mg, 1.24 mmol, 85.5% yield, 98.6% purity, HCl salt) as a yellow oil. This compound was used directly without further purification.

[0385] Intermediate AG [ka] Step A: To a solution of 4,6-dichloropicolinate methyl (4.50 g, 21.8 mmol, 1.00 equivalent) in dichloromethane (40.0 mL), DIBAL-H (1.0 M, 65.5 mL, 3.00 equivalent) was added dropwise over 10 minutes at -78°C, and the reaction mixture was stirred at -78°C for 2 hours. Next, the mixture was diluted with water (2.50 mL) dropwise under a nitrogen atmosphere at 0°C, followed by the addition of aqueous sodium hydroxide solution (2.50 mL, w / w=15%) and water (6.26 mL). The mixture was then stirred at 0°C for 30 minutes to obtain a suspension, which was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 30 / 1 to 10 / 1) to obtain (4,6-dichloropyridine-2-yl)methanol (2.40 g, 13.5 mmol, 61.7% yield) as a yellow oil.

[0386] 1 H NMR (400MHz, DMSO-d6) δ=7.65(s,1H), 7.52(s,1H), 5.69(t,J=6.0Hz,1H), 4.53(d,J=6.0Hz,2H).

[0387] Step B: To a solution of (4,6-dichloropyridine-2-yl)methanol (2.40 g, 13.5 mmol, 1.00 equivalent) in dichloromethane (20.0 mL), Dess Martin periodinane (11.4 g, 27.0 mmol, 8.35 mL, 2.00 equivalent) was gradually added at 0°C, and the mixture was stirred at 20°C for 2 hours. Next, the mixture was poured into water (10.0 mL) and stirred for 15 minutes, then saturated sodium thiosulfate aqueous solution (20.0 mL) was slowly added, and the mixture was stirred for a further 15 minutes. The suspension was filtered, the layers were separated, and the aqueous phase was extracted with DCM (20.0 mL x 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 10 / 1) to obtain 4,6-dichloropicoline aldehyde (1.60 g, 9.09 mmol, 67.4% yield) as red oil.

[0388] 1 H NMR (400MHz, DMSO-d6) δ = 9.87 (s, 1H), 8.14 (d, J = 1.6 Hz, 1H), 8.01 (d, J = 1.6 Hz, 1H).

[0389] Step C: To a solution of 4,6-dichloropicoline aldehyde (1.10 g, 6.25 mmol, 1.00 equivalent) in dichloromethane (10.0 mL), diethylaminosulfur trifluoride (2.01 g, 12.5 mmol, 1.65 mL, 2.00 equivalent) was added dropwise at -20°C, and the mixture was stirred at 25°C for 1 hour. Next, the mixture was slowly poured into a saturated sodium bicarbonate aqueous solution (10.0 mL) at 25°C, and the resulting solution was extracted with ethyl acetate (10.0 mL × 3). The combined organic phases were washed with brine (5.00 mL × 3), dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 20 / 1) to obtain 2,4-dichloro-6-(difluoromethyl)pyridine (1.00 g, 5.05 mmol, 80.8% yield) as a yellow oil.

[0390] 1 H NMR (400MHz, CD3OD) δ=7.75(s,1H), 7.74(s,1H), 6.82-6.55(m,1H).

[0391] Step D: To a solution of tributyl(1-ethoxyvinyl)tin (2.01 g, 5.56 mmol, 1.88 mL, 1.00 equivalent) and 2,4-dichloro-6-(difluoromethyl)pyridine (1.10 g, 5.56 mmol, 1.00 equivalent) in dioxane (10.0 mL), Pd(PPh3)2Cl2 (390 mg, 556 μmol, 0.10 equivalent) was added under a nitrogen atmosphere, and the mixture was stirred at 110°C for 12 hours. The reaction mixture was cooled to 25°C and slowly poured into saturated potassium fluoride aqueous solution (20.0 mL). The resulting aqueous solution was extracted with ethyl acetate (50.0 mL x 3), the combined organic layer was washed with brine (30.0 mL x 2), dried on anhydrous sodium, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 20 / 1) to obtain 4-chloro-2-(difluoromethyl)-6-(1-ethoxyvinyl)pyridine (1.20 g, 5.14 mmol, 92.5% yield) as a yellow oil, which was used directly in the next step.

[0392] To a solution of 4-chloro-2-(difluoromethyl)-6-(1-ethoxyvinyl)pyridine (1.00 g, 4.28 mmol, 1.00 equivalent) in dioxane (5.00 mL), aqueous hydrochloric acid (2.00 M, 4.28 mL, 2.00 equivalent) was added at 20°C, and the mixture was stirred at 20°C for 1 hour. Next, saturated sodium bicarbonate (15.0 mL) was added to adjust the pH of the mixture to pH=8, and the mixture was extracted with ethyl acetate (30.0 mL × 2). The combined organic phase was washed with brine (10.0 mL × 2), dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 10 / 1) to obtain 1-(4-chloro-6-(difluoromethyl)pyridine-2-yl)ethane-1-one (800 mg, 3.89 mmol, 90.9% yield) as a white solid.

[0393] 1 H NMR (400MHz, CD3OD) δ=8.10-8.16(m,1H), 7.95(d,J=1.6Hz,1H), 6.67-6.95(m,1H), 2.69(s,3H).

[0394] Step E: To a solution of 1-(4-chloro-6-(difluoromethyl)pyridine-2-yl)ethane-1-one (0.85 g, 4.13 mmol, 1.00 equivalent) and tert-butylcarbamate (1.45 g, 12.4 mmol, 3.00 equivalent) in dioxane (6.00 mL), cesium carbonate (2.69 g, 8.27 mmol, 2.00 equivalent), XPhos (394 mg, 827 μmol, 0.20 equivalent), and palladium acetate (92.8 mg, 413 μmol, 0.10 equivalent) were added under a nitrogen atmosphere, and the mixture was stirred at 90°C for 2 hours. Next, the mixture was cooled to 25°C, concentrated under reduced pressure, and the residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 10 / 1) to obtain tert-butyl (2-acetyl-6-(difluoromethyl)pyridine-4-yl) carbamate (1.00 g, 3.49 mmol, 84.5% yield) as a white solid. LCMS[M+1]+: 287.1.

[0395] Step F: To a solution of tert-butyl(2-acetyl-6-(difluoromethyl)pyridine-4-yl)carbamate (1.00 g, 3.49 mmol, 1.00 equivalent) and (S)-2-methylpropan-2-sulfinamide (508 mg, 4.19 mmol, 1.20 equivalent) in THF (10.0 mL), titanium(IV) ethoxide (7.97 g, 34.9 mmol, 7.24 mL, 10.0 equivalent) was added, and the mixture was stirred at 75°C for 12 hours. Next, the mixture was cooled to 25°C, poured into water (5.00 mL), then the suspension was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 5 / 1) to obtain tert-butyl(S)-(2-(1-((tert-butylsulfinyl)imino)ethyl)-6-(difluoromethyl)pyridine-4-yl)carbamate (1.00 g, 2.57 mmol, 73.5% yield) as a yellow solid.

[0396] 1 H NMR (400MHz, CD3OD) δ=8.30(s,1H), 7.94(d,J=1.6Hz,1H), 6.52-6.82(m,1H), 2.81(s,3H), 1.54(s,9H), 1.35(s,9H).

[0397] Step G: To a solution of tert-butyl(S)-(2-(1-((tert-butylsulfinyl)imino)ethyl)-6-(difluoromethyl)pyridine-4-yl)carbamate (1.00 g, 2.57 mmol, 1.00 equivalent) in THF (10.0 mL), L-selectlide (1.0 M, 976 mg, 5.14 mmol, 1.12 mL, 2.00 equivalent) was added dropwise at 0°C, and the mixture was stirred at 0-20°C for 1 hour. The mixture was poured into saturated ammonium chloride aqueous solution (15.0 mL), stirred for 10 minutes, and then extracted with ethyl acetate (15.0 mL x 3). The combined organic phase was washed with brine (15.0 mL x 3), dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 5 / 1) to obtain tert-butyl(2-((R)-1-(((S)-tert-butylsulfinyl)amino)ethyl)-6-(difluoromethyl)pyridine-4-yl)carbamate (550 mg, 1.26 mmol, 49.0% yield, 89.5% purity) as a white solid.

[0398] 1 H NMR (400MHz, CD3OD) δ=7.70(s,1H), 7.61(d,J=2.0Hz,1H), 6.41-6.77(m,1H), 4.55(q,J=6.8Hz,1H), 1.58(d,J=6.8Hz,3H), 1.53(s,9H), 1.23(s,9H).

[0399] SFC: Column: Chiralcel OD-3 50×4.6mm ID, 3um; Mobile phase: Phase A for CO2, Phase B for MeOH (0.05% DEA); Gradient elution: MeOH (0.05% DEA) in CO2 from 5% to 40%; Flow rate: 3 mL / min; Detector: PDA; Column temperature: 35℃; Back pressure: 100 Bar.

[0400] Step H: A solution of tert-butyl(2-((R)-1-(((S)-tert-butylsulfinyl)amino)ethyl)-6-(difluoromethyl)pyridine-4-yl)carbamate (450 mg, 1.15 mmol, 1.00 equivalent) in hydrochloric acid / dioxane (2.00 mL) was stirred at 0-20°C for 1 hour. The mixture was then concentrated under reduced pressure to obtain a mixture of (R)-2-(1-aminoethyl)-6-(difluoromethyl)pyridine-4-amine and tert-butyl(2-((R)-1-(((S)-tert-butylsulfinyl)amino)ethyl)-6-(difluoromethyl)pyridine-4-yl)carbamate as a white solid, which was used directly in the next step without purification. LCMS[M+1]+: 288.2.

[0401] 1 H NMR (400MHz, CD3OD) δ=7.74(s,1H), 7.65(d,J=1.6Hz,1H), 6.82-6.51(m,1H), 4.60-4.45(m,2H), 1.61(d,J=6.8Hz,3H), 1.54(s,9H).

[0402] Intermediate AH [ka] Step A: To a solution of 1-(2-fluoro-3-methylphenyl)ethane-1-one (1.00 g, 6.57 mmol, 1.00 equivalent) and (S)-2-methylpropane-2-sulfinamide (1.04 g, 8.54 mmol, 1.30 equivalent) in tetrahydrofuran (20.0 mL), titanium tetraisopropyl oxide (3.73 g, 13.1 mmol, 3.88 mL, 2.00 equivalent) was added under a nitrogen atmosphere, and the mixture was stirred at 70°C for 12 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25°C, poured into water (40.0 mL), stirred for 10 minutes to obtain a suspension, filtered, and the resulting aqueous solution was extracted with ethyl acetate (40.0 mL × 3). The combined organic layers were washed with brine (30.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 50 / 1~2 / 1) to obtain (S)-N-(1-(2-fluoro-3-methylphenyl)ethylidene)-2-methylpropane-2-sulfinamide (1.50 g, 5.87 mmol, 89.4% yield) as a yellow solid. LCMS[M+1]+: 256.2.

[0403] 1 H NMR(400MHz,DMSO-d6)δ=7.46(br t,J=6.8Hz,1H), 7.30-7.24(m,1H), 7.09-7.04(m,1H), 2.76(br d,J=2.8Hz,3H), 2.31(d,J=2.4Hz,3H), 1.31(s,9H).

[0404] Step B: To a solution of (S)-N-(1-(2-fluoro-3-methylphenyl)ethylidene)-2-methylpropane-2-sulfinamide (1.50 g, 5.87 mmol, 1.00 equivalent) in tetrahydrofuran (20.0 mL), L-selectlide (1.0 M, 11.7 mmol, 11.8 mL, 2.00 equivalent) was added under a nitrogen atmosphere at -78°C, and the mixture was stirred at -78°C for 2 hours. The reaction mixture was slowly poured into water (10.0 mL) and stirred for 10 minutes, and the resulting mixture was extracted with ethyl acetate (10.0 mL x 3). The combined organic layers were washed with brine (10.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 50 / 1 to 1 / 1) to obtain (S)-N-(1-(2-fluoro-3-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (900 mg, 3.50 mmol, 59.5% yield) as a yellow oil. LCMS[M+1]+: 258.4.

[0405] 1 H NMR(400MHz,DMSO-d6)δ=7.16(t,J=7.6Hz,1H), 7.13-7.08(m,1H), 7.04-6.99(m,1H ), 4.85(q,J=6.8Hz,1H), 2.28(d,J=2.0Hz,3H), 1.58(d,J=6.8Hz,3H), 1.20(s,9H).

[0406] Step C: To a solution of (S)-N-(1-(2-fluoro-3-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (900 mg, 3.50 mmol, 1.00 equivalent) in dichloromethane (5.00 mL, 5.72 equivalents), HCl (4.00 M in 1,4-dioxane, 5.00 mL, 5.72 equivalents) was added under a nitrogen atmosphere, and the mixture was stirred at 20°C for 1 hour. The mixture was concentrated to obtain 1-(2-fluoro-3-methylphenyl)ethane-1-amine (390 mg, crude, hydrochloride) as a yellow solid, which was used directly without further purification.

[0407] A solution of 1-(2-fluoro-3-methylphenyl)ethane-1-amine (300 mg, 1.96 mmol, 1.00 equivalent, hydrochloride), 1,7-dichloro-4-methylpyrido[3,4-d]pyridazine (419 mg, 1.96 mmol, 1.00 equivalent), N,N-diisopropylethylamine (506 mg, 3.92 mmol, 2.00 equivalent), and potassium fluoride (341 mg, 5.87 mmol, 0.14 mL, 3.00 equivalent) in dimethyl sulfoxide (5.00 mL) was stirred at 130°C for 1 hour under a nitrogen atmosphere. The mixture was then cooled to 25°C, poured into water (20.0 mL), and extracted with ethyl acetate (20.0 mL x 3). The combined organic layer was washed with brine (20.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC [column: Welch Xtimate C18 150×25mm×5um; mobile phase: phase A: water (0.05% HCl), phase B: acetonitrile; B%: 14%~44%] to obtain 7-chloro-N-(1-(2-fluoro-3-methylphenyl)ethyl)-4-methylpyrido[3,4-d]pyridazine-1-amine (100 mg, 0.30 mmol, 23.2% yield) as a yellow solid. LCMS[M+1]+: 331.2.

[0408] Racemic 7-chloro-N-(1-(2-fluoro-3-methylphenyl)ethyl)-4-methylpyrido[3,4-d]pyridazin-1-amine (200 mg, 0.60 mmol, 1.00 equivalent) was purified by SFC (column: DAIEL CHIRALPAK IG (250 mm × 30 mm, 10 μm); mobile phase: phase A: 0.1% NH4OH in MeOH, phase B: CO2; B%: 30%~30%) to obtain (R)-7-chloro-N-(1-(2-fluoro-3-methylphenyl)ethyl)-4-methylpyrido[3,4-d]pyridazin-1-amine as a yellow solid, with the first eluted isomer (80.0 mg, 0.24 mmol, 40.0% yield).

[0409] The following examples are intended to further illustrate certain specific embodiments of the present invention and are not intended to limit the scope of the invention.

[0410] Example 1-1 6,7-Dimethoxy-N-(1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)phthalazine-1-amine [ka] Step A: A mixture of 1-chloro-6,7-dimethoxyphthalazine (120 mg, 534 μmol, 1.00 equivalent), tert-butyl (2-(5-(1-aminoethyl)thiophen-3-yl)benzyl)(methyl)carbamate (130 mg, 374 μmol, 0.70 equivalent), BrettPhos Pd G3 (48.4 mg, 53.4 μmol, 0.10 equivalent), and potassium tert-butoxide (150 mg, 1.34 mmol, 2.50 equivalent) in toluene (3.00 mL) was degassed, purged three times with nitrogen, and then the reaction mixture was stirred under a nitrogen atmosphere at 100°C for 1 hour. The reaction mixture was cooled to 25°C, filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (SiO2, dichloromethane / methanol = 10 / 1) to obtain tert-butyl(2-(5-(1-((6,7-dimethoxyphthalazine-1-yl)amino)ethyl)thiophen-3-yl)benzyl)(methyl)carbamate (70.0 mg, 24.5% yield) as a brown solid. LCMS[M+1]: 535.5.

[0411] Step B: To a solution of tert-butyl(2-(5-(1-((6,7-dimethoxyphthalazine-1-yl)amino)ethyl)thiophen-3-yl)benzyl)(methyl)carbamate (60.0 mg, 112 μmol, 1.00 equivalent) in acetonitrile (1.00 mL), HCl (4.0 M in dioxane, 0.20 mL) was added. The reaction mixture was stirred at 25°C for 10 minutes, then the mixture was filtered and concentrated under reduced pressure at 25°C to obtain the residue. The residue was dissolved in methanol (2.00 mL) and the pH was adjusted to 7 with solid sodium bicarbonate (approximately 30.0 mg) to obtain a suspension. The suspension was filtered, and the filtrate was separated and purified by HPLC (column: Waters Xbridge 150×25mm×5um; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 19%~49%, 9 min) and lyophilization to obtain 6,7-dimethoxy-N-(1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)phthalazine-1-amine (16.6 mg, 33.8% yield, 99.6% purity) as a white solid. LCMS[M+1]: 435.1.

[0412] 1 H NMR(400MHz,CD3OD)δ 8.73(d,J=2.4Hz,1H), 7.75(s,1H), 7.51-7.46(m,1H), 7.43-7.37(m,3H), 7.35(d,J=5.2Hz,1H), 7.19(d,J=1.2Hz ,1H), 7.16(s,1H), 5.93-5.81(m,1H), 4.10(s,2H), 4.05(s,3H), 4.00(s,3H), 2.45(s,3H), 1.83(d,J=6.8Hz,3H).

[0413] Examples 1-2 (R)-7-(1-methyl-1H-pyrazole-4-yl)-N-(1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)phthalazine-1-amine [ka] Step A: To a solution of 7-bromophthalazine-1-ol (950 mg, 4.22 mmol, 1.00 equivalent) in acetonitrile (19.0 mL), phosphorus(V) oxychloride (2.27 g, 14.8 mmol, 1.37 mL, 3.50 equivalents) was added, and the reaction mixture was stirred at 80°C for 2 hours. The reaction mixture was cooled to 25°C, concentrated under vacuum, and the solvent was removed. The remaining residue was diluted with DCM (50.0 mL) cooled to 0°C, and the organic layer was adjusted to pH=7 with saturated sodium bicarbonate aqueous solution (30.0 mL). The organic phase was separated, washed with brine (30.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 7-bromo-1-chlorophthalazine (900 mg, 3.70 mmol, 87.6% yield) as a brown solid. LCMS[M+3]: 244.8.

[0414] 1 H NMR(400MHz, CDCl3)δ 9.44(d,J=0.8Hz,1H), 8.52-8.49(m,1H), 8.10(dd,J=2.0,8.8Hz,1H), 7.90(d,J=8.4Hz,1H).

[0415] Step B: To a solution of 7-bromo-1-chlorophthalazine (100 mg, 411 μmol, 1.00 equivalent) in DMSO (2.00 mL), tert-butyl(R)-(2-(5-(1-aminoethyl)thiophen-3-yl)benzyl)(methyl)carbamate (129 mg, 370 μmol, 0.90 equivalent), potassium fluoride (71.6 mg, 1.23 mmol, 28.8 μL, 3.00 equivalent), and diisopropylethylamine (106 mg, 821 μmol, 143 μL, 2.00 equivalent) were added. The reaction mixture was stirred under a nitrogen atmosphere at 130 °C for 4 hours. After that, the reaction mixture was cooled to 25 °C. Ethyl acetate (10.0 mL) and water (8.00 mL) were added to the reaction mixture to separate the layers, and the aqueous phase was extracted with ethyl acetate (10.0 mL × 2). The combined organic layers were washed with brine (10.0 mL x 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 1 / 1) to obtain tert-butyl(R)-(2-(5-(1-((7-bromophthalazine-1-yl))amino)ethyl)thiophen-3-yl)benzyl)(methyl)carbamate (80.0 mg, 35.2% yield) as a yellow solid. LCMS[M+1]: 553.0.

[0416] 1 H NMR(400MHz,CD3OD)δ 8.80(s,1H), 8.56(s,1H), 8.20(s,1H), 8.12-8.07(m,2H), 7.91(br d,J=8.4Hz,1H), 7.33-7.25(m,3H), 7.19(br d,J=7.2Hz,1H), 7.15-7.03(m,2H), 5.90-5.97(m,1H), 4.45(br d,J=14.8Hz,2H), 3.97(s,3H), 2.66(s,3H), 1.84(d,J=6.8Hz,3H), 1.46-1.29(m,9H).

[0417] Step D: To a solution of tert-butyl(R)-methyl(2-(5-(1-((7-(1-methyl-1H-pyrazole-4-yl)phthalazine-1-yl)amino)ethyl)thiophen-3-yl)benzyl)carbamate (18.0 mg, 32.5 μmol, 1.00 equivalent) in DCM (1.00 mL), TFA (770 mg, 6.75 mmol, 0.50 mL, 208 equivalents) was added. The reaction mixture was stirred at 25°C for 10 minutes. The reaction mixture was filtered and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex LunaC18 75×30mm×3um; mobile phase: [water (0.05% HCl)-ACN]; B%: 13%~33%) and lyophilization to obtain (R)-7-(1-methyl-1H-pyrazole-4-yl)-N-(1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)phthalazine-1-amine (9.02 mg, 55.7% yield, 91.1% purity) as an off-white solid. LCMS[M+1]: 455.2.

[0418] 1 H NMR(400MHz,CD3OD)δ 9.10(br s,1H), 8.49(s,1H), 8.39(dd,J=1.2,8.4Hz,1H), 8.29(s,1H), 8.23(br d,J=8.4Hz,1H), 8.17(s,1H), 8.08(s,1H), 7.60-7.57(m,1H), 7.50-7.45(m,2H), 7.44-7.40(m,1H), 7 .39-7.34(m,2H), 5.78(q,J=6.4Hz,1H), 4.30(s,2H), 4.04(s,2H), 4.01(s,3H), 2.62(s,3H), 1.98(br d, J = 6.8 Hz, 3H).

[0419] Examples 1-3 (R)-N-(1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)-7-morpholinophthalazine-1-amine [ka] Step A: A mixture of tert-butyl(R)-(2-(5-(1-((7-bromophthalazine-1-yl)amino)ethyl)thiophen-3-yl)benzyl)(methyl)carbamate (45.0 mg, 81.3 μmol, 1.00 equivalent), morpholine (10.6 mg, 122 μmol, 10.7 μL, 1.50 equivalent), Pd2(dba)3 (7.44 mg, 8.13 μmol, 0.10 equivalent), RuPhos (7.59 mg, 16.3 μmol, 0.20 equivalent), and potassium tert-butoxide (1.00 M in THF, 163 μL, 2.00 equivalent) in toluene (3.00 mL) was degassed, purged three times with nitrogen, and then the reaction mixture was stirred under a nitrogen atmosphere at 110°C for 1 hour. The reaction mixture was cooled to 25°C and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 20 / 1) to obtain tert-butyl(R)-methyl(2-(5-(1-((7-morpholinophthalazine-1-yl)amino)ethyl)thiophen-3-yl)benzyl)carbamate (40.0 mg, 57.2 μmol, 70.3% yield, 80.0% purity) as a yellow solid. LCMS[M+1]: 560.2.

[0420] 1 H NMR(400MHz,CDCl3)δ 8.81(s,1H), 7.72(d,J=8.8Hz,1H), 7.46-7.41(m,1H), 7.35-7.28(m,3H), 7.26-7.06(m,3H), 7.03(d,J=1.2Hz,1H), 6.15-5 .95(m,1H), 4.80-4.40(m,2H), 3.96-3.86(m,4H), 3.46-3.28(m,4H), 2.80-2.52(m,3H), 1.83(d,J=6.8Hz,3H), 1.42(s,9H).

[0421] Step B: To a solution of tert-butyl(R)-methyl(2-(5-(1-((7-morpholinophthalazine-1-yl)amino)ethyl)thiophen-3-yl)benzyl)carbamate (37.0 mg, 52.9 μmol, 1.00 equivalent) in acetonitrile (1.00 mL), HCl (4.00 M in dioxane, 0.50 mL) was added dropwise at 0°C, and the reaction mixture was stirred at 0°C for 30 minutes. Methanol (2.00 mL) was added to the mixture, and the pH was adjusted to 7 with solid sodium bicarbonate (approximately 30.0 mg) to obtain a suspension. The suspension was filtered, and the filtrate was concentrated under vacuum to obtain the residue. The residue was purified by preparative HPLC (column: Waters Xbridge 150×25mm×5um; mobile phase: [A: water (10mM NH4HCO3)-B: ACN]; B%: 22%~52%) to obtain (R)-N-(1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)-7-morpholinophthalazine-1-amine (18.3 mg, 38.5 μmol, 72.7% yield, 96.6% purity) as a white solid. LCMS[M+1]: 460.2.

[0422] 1 H NMR(400MHz,CD3OD)δ 8.66(s,1H), 7.82(dd,J=1.2,8.8Hz,1H), 7.65-7.60(m,1H), 7.55(d,J=2.0Hz,1H), 7.46-7.41(m,1H), 7.36-7.30(m,3H), 7.18 (d,J=5.2Hz,2H), 5.94(q,J=6.8Hz,1H), 3.93-3.87(m,4H), 3.81(s,2H), 3.49-3.43(m,4H), 2.28(s,3H), 1.84(d,J=6.8Hz,3H).

[0423] Examples 1-4 (R)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-morpholinophthalazine-1-amine [ka] Step A: To a solution of 7-bromo-1-chlorophthalazine (244 mg, 1.00 mmol, 1.00 equivalent) and (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethane-1-amine (242 mg, 1.00 mmol, 1.00 equivalent, hydrochloride) in DMSO (3.00 mL), potassium fluoride (175 mg, 3.00 mmol, 70.4 μL, 3.00 equivalent) and DIEA (259 mg, 2.00 mmol, 349 μL, 2.00 equivalent) were added, and the reaction mixture was stirred at 130°C for 12 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25°C, diluted with ethyl acetate (20.0 mL), the organic layer was washed with brine (20.0 mL x 2), dried on anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to obtain (R)-7-bromo-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)phthalazine-1-amine (280 mg, 683 μmol, 68.2% yield) as a brown solid. LCMS[M+1]: 409.9.

[0424] 1 H NMR(400MHz,CDCl3)δ 8.92(s,1H), 7.94(s,1H), 7.91(dd,J=1.6,8.4Hz,1H), 7.71(d,J=8.4Hz,1H), 7.68(d ,J=7.6Hz,1H), 7.58(d,J=8.0Hz,1H), 7.32-7.28(m,1H), 6.02-5.94(m,1H), 5.14(br d,J=6.4Hz,1H), 2.58(s,3H), 1.70(d,J=6.8Hz,3H).

[0425] Step B: To a solution of (R)-7-bromo-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)phthalazine-1-amine (30.0 mg, 73.1 μmol, 1.00 equivalent) and morpholine (12.7 mg, 146 μmol, 12.9 μL, 2.00 equivalent) in dioxane (1.00 mL), Pd2(dba)3 (6.70 mg, 7.31 μmol, 0.10 equivalent), RuPhos (6.82 mg, 14.6 μmol, 0.20 equivalent), and cesium carbonate (47.7 mg, 146 μmol, 2.00 equivalent) were added under a nitrogen atmosphere. The reaction mixture was stirred under a nitrogen atmosphere at 110 °C for 1 hour. The reaction mixture was cooled to 25 °C, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by preparative TLC (dichloromethane / methanol = 10 / 1) to obtain the crude product. The crude product was then purified by preparative HPLC (column: Waters Xbridge C18 150×50mm×10um; mobile phase: [A: water (10mM NH4HCO3), B: ACN]; B%: 40%~70%) to obtain (R)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-morpholinophthalazine-1-amine (11.0 mg, 26.2 μmol, 35.8% yield, 99.2% purity) as a white solid. LCMS[M+1]: 417.1.

[0426] 1 H NMR(400MHz,CD3OD)δ=8.56(s,1H), 7.79-7.75(m,1H), 7.72(d,J=8.0Hz,1H), 7.62-7.57(m,2H), 7.49(d,J=7.2Hz,1H), 7.25(t,J=7.6Hz,1H), 5.77(q,J=6.8Hz,1H), 3.94-3.84(m,4H), 3.51-3.42(m,4H), 2.61(s,3H), 1.64(d,J=7.2Hz,3H).

[0427] Following the instructions for General Reaction Scheme III and the preparations of Examples 1-1 to 1-4, the following compounds of formula (I) and Examples 1-5 to 1-50, shown in Table 1, were prepared. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9]

[0428] Example 2-1 (R)-N-(1-(4-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)-7-morpholinophthalazine-1-amine [ka] To a solution of (R)-N-(1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)-7-morpholinophthalazine-1-amine (15.0 mg, 32.6 μmol, 1.00 equivalent) in dimethylformamide (0.50 mL), potassium hydroxide (2.75 mg, 49.0 μmol, 1.50 equivalent) was added at 15°C, and the reaction mixture was stirred at 15°C for 1 hour. A solution of methyl 4-methylbenzenesulfonate (7.90 mg, 42.4 μmol, 1.3 equivalent) in dimethylformamide (0.20 mL) was added dropwise to the reaction mixture. After the addition was complete, the reaction mixture was heated to 50°C and stirred for 2 hours. Next, the reaction mixture was cooled to 25°C, and ethyl acetate (3.00 mL) and water (3.00 mL) were added to the mixture. The layers were separated, the organic phases were combined, washed twice with water (3.00 mL), and dried on anhydrous sodium sulfate to obtain the residue. The residue was purified by preparative HPLC (column: Waters Xbridge 150 × 25 mm × 5 μm; mobile phase: [water (0.05% ammonium hydroxide v / v)-ACN]; B%: 32%~62%, 10 min) to obtain (R)-N-(1-(4-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)-7-morpholinophthalazine-1-amine (1.61 mg, 3.39 μmol, 10.4% yield, 99.7% purity) as an off-white solid. LCMS[M+1]: 474.3.

[0429] 1 H NMR(400MHz,CD3OD)δ 8.65(s,1H), 7.81(d,J=8.8Hz,1H), 7.61(dd,J=2.4,9.2Hz,1H), 7.54(d,J=2.4Hz,1H), 7.48-7.41(m,1H), 7.37-7.29(m,3H), 7.21(d,J=1. 2Hz,1H), 7.18-7.12(m,1H), 5.91(q,J=6.8Hz,1H), 3.90-3.85(m,4H), 3.60(s,2H), 3.48-3.42(m,4H), 2.17(s,6H), 1.82(d,J=6.8Hz,3H).

[0430] Example 2-2 N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(((S)-pyrrolidine-3-yl)oxy)phthalazine-1-amine [ka] Step A: To a solution of (R)-7-bromo-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)phthalazine-1-amine (80.0 mg, 195 μmol, 1.00 equivalent) in toluene (2.00 mL), sodium hydride (15.6 mg, 390 μmol, 60.0% purity, 2.00 equivalent) was added at 0°C under a nitrogen atmosphere. Next, tert-butyl(S)-3-hydroxypyrrolidine-1-carboxylate (110 mg, 585 μmol, 3.00 equivalent), Pd2(dba)3 (17.9 mg, 19.5 μmol, 0.10 equivalent), and Tol-BINAP (132 mg, 195 μmol, 1.00 equivalent) were added to the reaction mixture, and the mixture was heated at 100°C for 1 hour. The reaction mixture was cooled to 25°C, poured into water (20.0 mL), and extracted with ethyl acetate (20.0 mL x 3). The combined organic phase was concentrated under vacuum to obtain the residue. The residue was purified by reverse-phase HPLC [water (0.1% TFA)-ACN] to obtain tert-butyl(S)-3-((4-(((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)phthalazine-6-yl)oxy)pyrrolidine-1-carboxylate (35.0 mg, 44.0 μmol, 23.0% yield, 65.0% purity) as a yellow solid. LCMS[M+1]: 517.0.

[0431] Step B: To a solution of tert-butyl(S)-3-((4-(((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)phthalazine-6-yl)oxy)pyrrolidine-1-carboxylate (35.0 mg, 44.0 μmol, 1.00 equivalent) in acetonitrile (1.00 mL), HCl (4.00 M in dioxane, 11.0 μL, 1.00 equivalent) was added dropwise at 0°C under a nitrogen atmosphere. The reaction mixture was stirred at 0°C for 30 minutes, then concentrated under vacuum to obtain the residue. The residue was purified by reverse-phase preparative HPLC (column: Phenomenex Gemini-NX C18 75×30mm×3um; mobile phase: [water (0.1% TFA)-ACN]; B%: 25%~35%) to obtain N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(((S)-pyrrolidine-3-yl)oxy)phthalazine-1-amine (8.01 mg, 18.2 μmol, 41.0% yield, 95% purity) as a yellow solid. LCMS[M+1]: 417.1.

[0432] 1 H NMR(400MHz,CD3OD)δ=9.15(s,1H), 8.28-8.21(m,2H), 7.80-7.72(m,2H), 7.59(d,J=7.6Hz,1H), 7.37-7.27(t,J=7.6H z,1H), 5.67-5.57(m,2H), 3.80-3.67(m,2H), 3.64-3.47(m,2H), 2.63(s,3H), 2.55-2.46(m,2H), 1.73(d,J=6.8Hz,3H).

[0433] Following the instructions for General Reaction Scheme III and the preparation of Example 2-2, the following compounds of formula (I) and Examples 2-3 to 2-12, shown in Table 2, were prepared. [Table 2-1] [Table 2-2]

[0434] Example 3-1 (R)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(piperazin-1-yl)pyrido[3,4-d]pyridazin-1-amine [ka] Step A: To a solution of 1,7-dichloropyrido[3,4-d]pyridazine (40.0 mg, 200 μmol, 1.00 equivalent) and (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethane-1-amine (40.6 mg, 200 μmol, 1.00 equivalent) in DMSO (1.00 mL), diisopropylethylamine (77.5 mg, 600 μmol, 105 μL, 3.00 equivalent) and potassium fluoride (34.8 mg, 600 μmol, 14.05 μL, 3.00 equivalent) was added under a nitrogen atmosphere. The reaction mixture was stirred at 130 °C for 1 hour under a nitrogen atmosphere, then cooled to 25 °C, poured into water (3.00 mL), and stirred for 5 minutes. The aqueous phase was extracted with ethyl acetate (5.00 mL x 3), the combined organic phase was washed with brine (3.00 mL x 2), dried on anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 1 / 1) to obtain (R)-7-chloro-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[3,4-d]pyridazine-1-amine (30.0 mg, 81.8 μmol, 40.9% yield) as a yellow solid. LCMS[M+1]: 367.2.

[0435] 1 H NMR(400MHz,CD3OD)δ=9.14(s,1H), 8.95(s,1H), 8.49(s,1H), 7.69(d,J=7.6Hz,1H), 7.51(d,J =7.6Hz,1H), 7.26(t,J=8.0Hz,1H), 5.76(q,J=6.8Hz,1H), 2.63(s,3H), 1.64(d,J=6.8Hz,3H).

[0436] Step B: To a solution of (R)-7-chloro-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[3,4-d]pyridazine-1-amine (18.0 mg, 49.1 μmol, 1.00 equivalent) and tert-butylpiperazine-1-carboxylate (13.7 mg, 73.6 μmol, 1.50 equivalent) in dioxane (0.50 mL), potassium tert-butoxide (1.00 M, 98.2 μL, 2.00 equivalent) and RuPhos-Pd-G3 (4.10 mg, 4.91 μmol, 0.10 equivalent) was added under a nitrogen atmosphere. The reaction mixture was stirred at 100 °C for 1 hour, then cooled to 25 °C, and concentrated under vacuum to obtain the residue. The residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 1 / 1) to obtain tert-butyl(R)-4-(1-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4-d]pyridazin-7-yl)piperazine-1-carboxylate (18.0 mg, crude) as a yellow solid. LCMS[M+1]: 517.3.

[0437] Step C: To a solution of tert-butyl(R)-4-(1-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4-d]pyridazin-7-yl)piperazine-1-carboxylate (11.0 mg, 21.3 μmol, 1.00 equivalent) in acetonitrile (1.00 mL), HCl in dioxane (3 M, 0.50 mL) was added. The reaction mixture was stirred at 0°C for 1 hour, then concentrated under vacuum to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150×25mm×10um; mobile phase: [water (0.1% TFA)-ACN]; B%: 10%~40%) to obtain (R)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(piperazin-1-yl)pyrido[3,4-d]pyridazin-1-amine (4.50 mg, 8.48 μmol, 39.8% yield, trifluoroacetate) as a white solid. LCMS[M+1] = 417.1.

[0438] 1H NMR(400MHz,CD3OD)δ=9.18(s,1H), 9.05(s,1H), 7.76(s,1H), 7.71(d,J=8.0Hz,1H), 7.56(d,J=7.2Hz,1H), 7.3 6-7.27(m,1H), 5.58(q,J=6.8Hz,1H), 4.30-4.21(m,4H), 3.50-3.38(m,4H), 2.61(s,3H), 1.69(d,J=6.8Hz,3H).

[0439] SFC: Chiralpak OJ-3 (50 × 4.6 mm ID, 3 μm); Mobile phase: Phase A for CO2, Phase B for MeOH (0.05% DEA); Gradient elution: 5% to 40% of 50% MeOH (0.05% DEA) in CO2. Flow rate: 3 mL / min; Detector: PDA; Column temperature: 35°C; Back pressure: 100 Bar.

[0440] Following the instructions for General Reaction Scheme III and the preparation of Example 3-1, the following compounds of formula (I) and Examples 3-2 to 3-6, shown in Table 3, were prepared. [Table 3]

[0441] Example 4-1 (R)-6,7-dimethoxy-4-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)phthalazine-1-amine [ka] A mixture of 1-chloro-6,7-dimethoxy-4-methylphthalazine (100 mg, 419 μmol, 1.00 equivalent), (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethane-1-amine (85.1 mg, 419 μmol, 1.00 equivalent), BrettPhos Pd G3 (38.0 mg, 41.9 μmol, 0.10 equivalent), and potassium tert-butoxide (1.00 M, 1.26 mL, 3.00 equivalent) in toluene (2.00 mL) was degassed and purged three times with nitrogen. The reaction mixture was stirred at 100°C for 1 hour under a nitrogen atmosphere, then cooled to 25°C, filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100×25mm×5um; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 35%~65%) to obtain (R)-6,7-dimethoxy-4-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)phthalazine-1-amine (8.24 mg, 20.3 μmol, 4.84% yield, 99.8% purity) as a white solid. LCMS[M+1]: 406.2.

[0442] 1 H NMR(400MHz,DMSO-d6)δ=7.83(s,1H), 7.76(d,J=7.6Hz,1H), 7.51(d,J=8.0Hz,1H), 7.39(d,J=6.8Hz,1H), 7.3 3-7.27(m,1H), 7.22(s,1H), 5.73-5.64(m,1H), 4.01(s,3H), 3.95(s,3H), 2.58(s,6H), 1.55(d,J=7.2Hz,3H).

[0443] Following the instructions for teaching General Reaction Scheme IV and preparing Example 4-1, the following compounds of Formula (I) and Examples 4-2 to 4-4, shown in Table 4, were prepared. [Table 4]

[0444] Example 5-1 (R)-N-(1-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)-4-isopropyl-6,7-dimethoxyphthalazine-1-amine [ka] Step A: A mixture of (R)-1-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethane-1-amine (200 mg, 768 μmol, 0.90 equivalents), 1,4-dichloro-6,7-dimethoxyphthalazine (221 mg, 853 μmol, 1.00 equivalent), N,N-diisopropylethylamine (331 mg, 2.56 mmol, 446 μL, 3.00 equivalents), and potassium fluoride (149 mg, 2.56 mmol, 60.0 μL, 3.00 equivalents) in DMSO (3.00 mL) was stirred at 130 °C for 12 hours. The reaction mixture was then cooled to 25 °C, followed by the addition of ethyl acetate (5.00 mL) and water (8.00 mL) to separate the layers. The aqueous phase was extracted with ethyl acetate (10.0 mL x 2), the combined organic layers were washed with brine (10.0 mL x 2), dried over sodium sulfate, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 1 / 1) to obtain ((R)-4-chloro-N-(1-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)-6,7-dimethoxyphthalazine-1-amine (100 mg, 24.3% yield) as a yellow solid. LCMS[M+1]: 483.0.

[0445] 1 H NMR(400MHz,CDCl3)δ=7.53-7.49(m,1H), 7.44(s,1H), 7.44-7.40(m,1H), 7.34-7.29(m,2H), 7.13-7.05(m,2H) ), 6.99(s,1H), 6.06-5.96(m,1H), 4.09(s,3H), 4.07(s,3H), 3.60(s,2H), 2.27(s,6H), 1.84(d,J=6.4Hz,3H).

[0446] Step B: To a solution of (R)-4-chloro-N-(1-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)-6,7-dimethoxyphthalazine-1-amine (40.0 mg, 82.8 μmol, 1.00 equivalent) and iron(III) acetylacetonate (80.0 mg, 226 μmol, 2.74 equivalents) in THF (1.00 mL) and 1-methyl-2-pyrrolidinone (0.01 mL), isopropylmagnesium chloride (3.00 M in THF, 600 μL, 21.7 equivalents) was added dropwise at 0°C. After addition, the reaction mixture was stirred at 25°C for 10 minutes. The reaction mixture was quenched by adding saturated ammonium chloride solution (5.00 mL) and extracted with ethyl acetate (1.00 mL x 3). The combined organic layers were washed with brine (2.00 mL x 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150 x 25 mm x 10 μm; mobile phase: [water (0.1% TFA)-ACN]; B%: 16%~46%), lyophilized, and (R)-N-(1-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)-4-isopropyl-6,7-dimethoxyphthalazine-1-amine (10.3 mg, 20.4% yield, 99.0% purity, trifluoroacetate) as an off-white solid. LCMS[M+1]: 491.3.

[0447] 1 H NMR(400MHz,CD3OD)δ=8.11(s,1H), 7.68(s,1H), 7.66-7.63(m,1H), 7.56-7.47(m,3H), 7.26-7.21(m,1H), 7.04(d,J=3.6Hz,1H), 5 .73-5.60(m,1H), 4.52(s,2H), 4.12(s,3H), 4.11(s,3H), 3.97-3.88(m,1H), 2.73(s,6H), 1.91(d,J=6.8Hz,3H), 1.53-1.42(m,6H).

[0448] SFC conditions: Column: Chiralcel OD-3 50×4.6mm ID, 3um; Mobile phase: Phase A for CO2, Phase B for MeOH (0.05% DEA); Gradient elution: MeOH (0.05% DEA) in CO2 from 5% to 40%; Flow rate: 3 mL / min; Detector: PDA; Column temperature: 35°C; Back pressure: 100 Bar.

[0449] Following the instructions for teaching General Reaction Scheme I and preparing Example 5-1, the following compounds of Formula (I) and Examples 5-2 to 5-3, shown in Table 5, were prepared. [Table 5]

[0450] Example 5-4 (R)-N-(1-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)-6,7-dimethoxy-4-(trifluoromethyl)phthalazine-1-amine [ka] Step A: To a solution of 2-bromo-4,5-dimethoxybenzoic acid (0.30 g, 1.15 mmol, 1.00 equivalent) in tetrahydrofuran (20.0 mL), n-BuLi (1.60 M, 1.72 mL, 2.40 equivalents) was added under a nitrogen atmosphere at -78°C. After stirring at -78°C for 1 hour, ethyl 2,2,2-trifluoroacetate (163 mg, 1.15 mmol, 159 μL, 1.00 equivalent) was added dropwise at the same temperature. The mixture was stirred at -78°C for 1 hour, warmed to 20°C, and stirred at 20°C for 3 hours. The reaction mixture was poured into ice water (20.0 mL) and extracted with ethyl acetate (20.0 mL x 3). The combined organic phase was washed with brine (20.0 mL x 3), dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 to 0 / 1) to obtain 4,5-dimethoxy-2-(2,2,2-trifluoroacetyl)benzoic acid (0.10 g, 30.9% yield) as a yellow oil. LCMS[M+1] += 279.0.

[0451] 1 H NMR (400MHz, CDCl3) δ=7.30(s,1H), 7.11(s,1H), 4.03(s,3H), 3.98(s,3H).

[0452] Step B: To a suspension of 4,5-dimethoxy-2-(2,2,2-trifluoroacetyl)benzoic acid (0.10 g, 359 μmol, 1.00 equivalent) in ethanol (10.0 mL), NH2NH2·H2O (180 mg, 3.59 mmol, 175 μL, 10.0 equivalent) was added at 20°C. The mixture was stirred at 100°C for 3 hours. After completion, the reaction product was concentrated under reduced pressure to obtain 6,7-dimethoxy-4-(trifluoromethyl)phthalazine-1(2H)-one (80.0 mg, crude) as a yellow solid. LCMS[M+1] + = 316.1.

[0453] 1 H NMR (400MHz, DMSO-d6) δ=7.70(s,1H), 7.15(s,1H), 3.98(s,3H), 3.96(s,3H).

[0454] Step C: To a solution of 6,7-dimethoxy-4-(trifluoromethyl)phthalazine-1(2H)-one (300 mg, 1.09 mmol, 1.00 equivalent) in POCl3 (4.95 g, 32.3 mmol, 3.00 mL, 29.5 equivalents), N,N-diisopropylethylamine (707 mg, 5.47 mmol, 953 μL, 5.00 equivalent) was added at 25°C. The mixture was stirred at 100°C for 30 minutes. The reaction mixture was concentrated under reduced pressure to obtain a residue. Next, it was diluted with ethyl acetate (10.0 mL), poured into ice water (10.0 mL), and extracted with ethyl acetate (10.0 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to obtain 1-chloro-6,7-dimethoxy-4-(trifluoromethyl)phthalazine (50.2 mg, 171 μmol, 15.7% yield) as a yellow solid. LCMS[M+1] + =293.0.

[0455] 1 H NMR (500MHz, CDCl3) δ=7.60(s,1H), 7.44(d,J=1.0Hz,1H), 4.15(s,3H), 4.12(s,3H).

[0456] Step D: To a solution of (R)-1-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethane-1-amine (50.0 mg, 168 μmol, 1.00 equivalent, HCl) and 1-chloro-6,7-dimethoxy-4-(trifluoromethyl)phthalazine (49.3 mg, 168 μmol, 1.00 equivalent) in DMSO (1.00 mL), N,N-diisopropylethylamine (87.1 mg, 674 μmol, 117 μL, 4.00 equivalent) and potassium fluoride (2.94 mg, 50.5 μmol, 1.18 μL, 0.30 equivalent) was added. After completion, the reaction mixture was filtered, and the residue was purified by preparative HPLC (column: Agela DuraShell C18 150×25mm×5um; mobile phase: phase A: [water (0.05% NH3H2O ​​+ 10mM NH4HCO3)], phase B: acetonitrile; B%: 60%~90%) to obtain (R)-N-(1-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)-6,7-dimethoxy-4-(trifluoromethyl)phthalazine-1-amine (4.51 mg, 8.72 μmol, 5.18% yield, 99.9% purity) as a white solid. LCMS[M+1] + = 517.1.

[0457] 1 H NMR(500MHz,CDCl3)δ=7.51-7.46(m,1H), 7.43(dd,J=1.5,7.0Hz,1H), 7.36(d,J=1.5Hz,1H), 7.35-7.28(m,2H), 7.13(s,2H), 6.99(br s,1H), 6.20-6.13(m,1H), 5.39(br s,1H), 4.08(s,3H), 4.07(s,3H), 3.53(br s,2H), 2.25(br s,6H), 1.87(d,J=6.5Hz,3H).

[0458] Example 6-1 (R)-4-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(4-methylpiperazine-1-yl)phthalazine-1-amine [ka] Step A: Methyl 5-bromo-2-iodobenzoate (5.00 g, 14.7 mmol, 1.00 equivalent), tributyl (1-ethoxyvinyl) stannan (5.60 g, 15.4 mmol, 5.20 mL, 1.05 equivalent), and Pd(PPh3)2Cl2 (309 mg, 440 μmol, 0.03 equivalent) were degassed from dioxane (50.0 mL), purged three times with nitrogen, and then the reaction mixture was stirred under a nitrogen atmosphere at 80°C for 10 hours. The reaction mixture was cooled to 25°C, quenched with added water (50.0 mL), and then extracted with ethyl acetate (50.0 mL x 3). The combined organic layers were washed with brine (20.0 mL x 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain methyl 5-bromo-2-(1-ethoxyvinyl)benzoate (6.00 g, crude) as a yellow oil, which was used directly in the next step.

[0459] Step B: To a solution of 5-bromo-2-(1-ethoxyvinyl)methylbenzoate (6.00 g, crude) in THF (50.0 mL), aqueous hydrochloric acid (10%, 25.0 mL) was added. The reaction mixture was stirred at 20°C for 1 hour. Water (50.0 mL) was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (30.0 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0~50 / 1) to obtain 2-acetyl-5-bromobenzoate (2.50 g, 67.0% yield) as yellow oil.

[0460] 1 H NMR (400MHz, CDCl3) δ=7.97(d,J=2.0Hz,1H), 7.70(dd,J=2.0,8.2Hz,1H), 7.32(d,J=8.4Hz,1H), 3.91(s,3H), 2.53(s,3H).

[0461] Step C: To a solution of 2-acetyl-5-bromomethylbenzoate (1.50 g, 5.83 mmol, 1.00 equivalent) in ethanol (30.0 mL), hydrazine hydrate (876 mg, 17.5 mmol, 851 μL, 3.00 equivalent) was added. The reaction mixture was stirred at 95°C for 30 minutes. Next, the reaction mixture was cooled to 25°C and concentrated under reduced pressure to obtain a residue. The residue was pulverized with ethanol for 10 minutes to obtain a suspension, which was filtered. The filter cake was collected and dried under vacuum to obtain 7-bromo-4-methylphthalazine-1(2H)-one (0.70 g, 2.93 mmol, 50.2% yield) as a white solid. LCMS[M+1]+: 239.0.

[0462] 1 H NMR (400MHz, DMSO-d6) δ=12.57(br s,1H), 8.32(d,J=2.0Hz,1H), 8.11(dd,J=2.0,8.4Hz,1H), 7.88(d,J=8.4Hz,1H), 2.50(s,3H).

[0463] Step D: 7-bromo-4-methylphthalazine-1-ol (1.00 g, 4.18 mmol, 1.00 equivalent), 1-methylpiperazine (628 mg, 6.27 mmol, 696 μL, 1.50 equivalent), RuPhos (195 mg, 418 μmol, 0.10 equivalent), Pd2(dba)3 (192 mg, 209 μmol, 0.05 equivalent), and t-BuOK (1 M in THF, 8.37 mL, 2.00 equivalent) were degassed, purged three times with N2, and the mixture was stirred under an N2 atmosphere at 110°C for 1.5 hours. The reaction mixture was quenched by adding water (20 mL) and then extracted with SiO2 (10 mL x 3). The combined organic layers were washed with brine (5 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was pulverized with siRNA (3 mL) for 10 minutes to obtain 4-methyl-7-(4-methylpiperazin-1-yl)phthalazine-1(2H)-one (800 mg, 3.10 mmol, 74.0% yield) as a yellow solid. LCMS[M+1]+: 259.1.

[0464] 1 H NMR(400MHz,DMSO-d6)δ=12.13(s,1H), 7.74(d,J=8.8Hz,1H), 7.56(dd,J=2.8,9.0Hz,1H ), 7.50(d,J=2.6Hz,1H), 3.40-3.34(m,4H), 2.49-2.45(m,4H), 2.43(s,3H), 2.23(s,3H).

[0465] Step E: 4-methyl-7-(4-methylpiperazin-1-yl)phthalazine-1(2H)-one (100 mg, 387 μmol, 1.00 equivalent) was dissolved in phosphorus oxychloride (1.61 g, 10.5 mmol, 976 μL, 27.1 equivalents). The mixture was stirred at 110°C for 16 hours. The reaction mixture was then cooled to 25°C and concentrated under vacuum to obtain the residue. The residue was dissolved in water (10.0 mL), adjusted to pH=9 with saturated sodium sulfate, and extracted with ethyl acetate (5.00 mL × 2). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to obtain 4-chloro-1-methyl-6-(4-methylpiperazin-1-yl)phthalazine (70.0 mg, crude) as a brown solid, which was used directly without purification. LCMS[M+1]+: 277.1.

[0466] Step F: To a solution of (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethane-1-amine (48.5 mg, 238 μmol, 1.10 equivalents) and (Cesium fluoride (98.8 mg, 650 μmol, 24.0 μL, 3.00 equivalents)) in dimethyl sulfoxide (3.00 mL), cesium fluoride (98.8 mg, 650 μmol, 24.0 μL, 3.00 equivalents) and N,N-diisopropylethylamine (140 mg, 1.08 mmol, 189 μL, 5.00 equivalents) were added. The mixture was then stirred at 120 °C for 16 hours. Next, the reaction mixture was poured into water (1.50 mL) and purified by preparative HPLC (column: Boston Green ODS 150 × 30 mm × 5 μm; mobile phase: [water (0.1% TFA)-ACN]; B%: 25%~45%, 10 min). The product was further purified by preparative HPLC (column: Agela DuraShell C18 150 × 25 mm × 5 μm; mobile phase: [water (0.05% NH3H2O ​​+ 10 mM NH4HCO3)-ACN]; B%: 38%~68%, 10 min) to obtain (R)-4-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(4-methylpiperazine-1-yl)phthalazine-1-amine (17.0 mg, 3.83 μmol, 17.6% yield, 99.9% purity) as a white solid. LCMS[M+1]+:444.1.

[0467] 1 H NMR(500MHz,CD3OD)δ=7.91(d,J=9.50Hz,1H), 7.70(d,J=8.50Hz,1H), 7.55-7.63( m,2H), 7.48(d,J=8.00Hz,1H), 7.23(t,J=7.50Hz,1H), 5.75-5.70(m,1H), 3.55(br s,4H), 2.68(br t,J=5.00Hz,4H), 2.59-2.63(m,6H), 2.40(s,3H), 1.63(d,J=7.00Hz,3H).

[0468] Example 6-2 (R)-4-methyl-N-(1-(5-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)-7-morpholinopyrido[3,4-d]pyridazine-1-amine [ka] Step A: To a solution of 5-bromo-2-chloroisonicotinic acid (12.0 g, 50.6 mmol, 1.00 equivalent) in MeOH (100 mL), SOCl2 (7.25 g, 60.9 mmol, 4.42 mL, 1.20 equivalent) was added dropwise. The mixture was then heated to 75°C and stirred for 8 hours. The reaction mixture was then concentrated under reduced pressure to obtain a residue. The residue was diluted with Depositphotos (100 mL), washed with saturated NaHCO3 (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain methyl 5-bromo-2-chloroisonicotinate (12.0 g, crude) as a yellow oil. LCMS[M+1]+: 252.0.

[0469] 1 H NMR (400MHz, DMSO-d6) δ = 8.78 (s, 1H), 7.89 (s, 1H), 3.91 (s, 3H).

[0470] Step B: Methyl 5-bromo-2-chloroisonicotinate (11.0 g, 43.92 mmol, 1.00 equivalent), tributyl (1-ethoxyvinyl) stannan (16.7 g, 46.1 mmol, 15.6 mL, 1.05 equivalent), and Pd(PPh3)2Cl2 (1.23 g, 1.76 mmol, 0.04 equivalent) were degassed from dioxane (110 mL), purged three times with N2, and the mixture was then heated at 80°C for 16 hours under an N2 atmosphere. Next, the reaction mixture was quenched with added water (400 mL) and then extracted with SiO2 (150 mL x 3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain methyl 2-chloro-5-(1-ethoxyvinyl) isonicotinate (10.6 g, crude) as a yellow oil.

[0471] Step C: To a solution of methyl 2-chloro-5-(1-ethoxyvinyl) isonicotinate (10.6 g, 43.9 mmol, 1.00 equivalent) in THF (100 mL), HCl (102 g, 280 mmol, 100 mL, 10% purity in water, 6.38 equivalents) was added dropwise, and the mixture was stirred at 20°C for 16 hours. Next, the reaction mixture was quenched by adding NaHCO3 (300 mL) at 0°C, and then extracted with RINKAN (100 mL x 3). The combined organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0~3 / 1) to obtain 5-acetyl-2-chloromethyl isonicotinate (4.50 g, 21.1 mmol, 48.0% yield) as a white solid.

[0472] 1 H NMR (400MHz, DMSO-d6) δ = 8.98 (s, 1H), 7.85 (s, 1H), 3.84 (s, 3H), 2.61 (s, 3H).

[0473] Step D: To a solution of 5-acetyl-2-chloromethyl isonicotinate (1.00 g, 4.68 mmol, 1.00 equivalent) in EtOH (15.0 mL), hydrazine hydrate (703 mg, 14.0 mmol, 683 μL, 3.00 equivalent) was added, and the mixture was stirred at 95°C for 30 minutes. The reaction mixture was then filtered, and the filter cake was concentrated under reduced pressure to obtain a residue, from which 7-chloro-4-methylpyrido[3,4-d]pyridazin-1(2H)-one (0.85 g, crude) was obtained as a white solid. LCMS[M+1]+: 196.1.

[0474] 1 H NMR (400MHz, DMSO-d6) δ = 9.20 (s, 1H), 8.10 (s, 1H), 2.58 (s, 3H).

[0475] Step E: 7-chloro-4-methylpyrido[3,4-d]pyridazine-1(2H)-one (750 mg, 3.83 mmol, 1.00 equivalent), morpholine (668 mg, 7.67 mmol, 675 μL, 2.00 equivalent), tBuOK (1.00 M in THF, 11.5 mL, 3.00 equivalent), RuPhos (179 mg, 383 μmol, 0.10 equivalent), and Pd2(dba)3 (176 mg, 192 μmol, 0.05 equivalent) were degassed from dioxane (10.0 mL), purged three times with nitrogen, and the mixture was stirred under a nitrogen atmosphere at 110°C for 3 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 (250*70 mm, 15 μm); mobile phase: [water (0.05% HCl)-ACN]; B%: 10%~40%) to obtain 4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1(2H)-one (500 mg, 2.03 mmol, 49.2% yield) as a white solid. LCMS[M+1]+: 247.0.

[0476] 1 H NMR (400MHz, DMSO-d6) δ=12.26(s,1H), 8.89(s,1H), 7.23(s,1H), 3.75-3.70(m,4H), 3.68-3.63(m,4H), 2.46(s,3H).

[0477] Step F: A solution of methyl-7-morpholinopyrid[3,4-d]pyridazin-1(2H)-one (500 mg, 2.03 mmol, 1.00 equivalent) in POCl3 (6.23 g, 40.6 mmol, 3.77 mL, 20.0 equivalents) was stirred at 110°C for 3 hours. The reaction mixture was then concentrated under reduced pressure to remove POCl3. The residue was diluted with H2O (100 mL), then adjusted to pH=8 using NaHCO3 solid, and then extracted with ethyl acetate (50.0 mL × 3). The combined organic layers were washed with brine (50.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 4-(1-chloro-4-methylpyrido[3,4-d]pyridazin-7-yl)morpholine (500 mg, crude) as a yellow solid. LCMS[M+1]+: 264.9.

[0478] 1 H NMR (400MHz, CDCl3) δ=9.13(s,1H), 6.89(s,1H), 3.92-3.86(m,4H), 3.81-3.75(m,4H), 2.91(s,3H).

[0479] Step G: In a glove box, a mixture of 4-(1-chloro-4-methylpyrido[3,4-d]pyridazin-7-yl)morpholine (50.0 mg, 189 μmol, 1.00 equivalent) and tert-butyl(R)-(2-(5-(1-aminoethyl)thiophen-2-yl)benzyl)(methyl)carbamate (65.5 mg, 189 μmol, 1.00 equivalent) in dimethyl sulfoxide (2.00 mL) was mixed with cesium fluoride (57.4 mg, 378 μmol, 13.9 μL, 2.00 equivalent) and N,N-diisopropylethylamine (48.8 mg, 378 μmol, 65.8 μL, 2.00 equivalent). The mixture was stirred at 130 °C for 3 hours, then cooled to room temperature, water (30.0 mL) was added to the reaction mixture, and it was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (20.0 mL), dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Agela DuraShell C18 150 × 25 mm × 5 μm, using water (0.04% NH4OH + 10 mM NH4HCO3) and acetonitrile as eluents; mobile phase A: water (0.04% NH3H2O ​​+ 10 mM NH4HCO3)-ACN, mobile phase B: acetonitrile; gradient: 24%~54%B) to obtain tert-butyl(R)-methyl(2-(5-(1-((4-methyl-7-morpholinopyrid[3,4-d]pyridazin-1-yl)amino)ethyl)thiophen-2-yl)benzyl)carbamate (20.0 mg, 34.8 μmol, 18.4% yield) as a yellow solid. LCMS[M+1]+:575.4.

[0480] 1H NMR(400MHz,CD3OD)δ=9.25(s,1H), 7.42(s,1H), 7.17-7.37(m,5H), 7.10(d,J=3.6Hz,1H), 6.86(br s,1H), 5.59-5.68(m,1H), 4.46-4.52(m,2H), 3.92(br s,4H), 3.76-3.84(m,4H), 2.84(s,3H), 2.70(s,3H), 1.80(d,J=7.2Hz,3H), 1.45(br s,9H).

[0481] Step H: Trifluoroacetic acid (0.20 mL) was added to a mixture of tert-butyl(R)-methyl(2-(5-(1-((4-methyl-7-morpholinopyrid[3,4-d]pyridazin-1-yl)amino)ethyl)thiophen-2-yl)benzyl)carbamate (20.0 mg, 34.8 μmol, 1.00 equivalent) in dichloromethane (1.00 mL). After completion, the mixture was concentrated, and the residue was purified by preparative HPLC (column: Agela DuraShell C18 150×25mm×5um, using water (0.04% NH3H2O ​​+ 10mM NH4HCO3) and acetonitrile as eluents; mobile phase A: water (0.04% NH4OH + 10mM NH4HCO3), mobile phase B: acetonitrile; gradient: 35%~65%B) to obtain (R)-4-methyl-N-(1-(5-(2-((methylaminomethyl)phenyl)thiophen-2-yl)ethyl)-7-morpholinopyrid[3,4-d]pyridazine-1-amine (4 mg, 8.43 μmol, 24.2% yield) as a white solid. LCMS[M+1]+: 475.3.

[0482] 1 H NMR(400MHz,CD3OD)δ=9.04(s,1H), 7.43(br d,J=6.4Hz,1H), 7.25-7.36(m,4H), 7.08(d,J=2.8Hz,1H), 6.92(d,J=3.2Hz,1H), 5.83(br d,J=6.8Hz,1H), 3.80-3.86(m,6H), 3.70-3.77(m,4H), 2.69(s,3H), 2.28(s,3H), 1.79(d,J=6.8Hz,3H).

[0483] The following compounds of formula (I) and examples 6-3 to 6-19, shown in Table 6, were prepared according to the procedures described in the instructions for general reaction schemes II and IV and the preparation of Examples 6-1, 6-2, 10-1, and 10-2. [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4]

[0484] Example 7-1 4-Methyl-N-((R)-1-(5-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)-7-(((S)-tetrahydrofuran-3-yl)oxy)phthalazine-1-amine [ka] Step A: Trifluoromethylsulfonyltrifluoromethanesulfonate (11.7 g, 41.3 mmol, 6.81 mL, 2.00 equivalent) was slowly added dropwise to a mixture of 1-(4-(benzyloxy)-2-hydroxyphenyl)ethane-1-one (5.00 g, 20.6 mmol, 1.00 equivalent) and pyridine (4.90 g, 61.9 mmol, 5.00 mL, 3.00 equivalent) in DCM (100 mL) at 0°C under a nitrogen atmosphere. The reaction mixture was then stirred at 20°C for 16 hours. The reaction mixture was poured into water (100 mL) and stirred for 5 minutes. The aqueous phase was extracted with DCM (50.0 mL x 3). The combined organic phase was washed with brine (50.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to obtain 2-acetyl-5-(benzyloxy)phenyltrifluoromethanesulfonate (7.40 g, 17.8 mmol, 86.2% yield, 90% purity) as a yellow solid. LCMS[M+1]+: 374.8.

[0485] 1 H NMR (400MHz, CDCl3) δ=7.85(d,J=8.8Hz,1H), 7.44-7.36(m,5H), 7.03(dd,J=2.4,8.8Hz,1H), 6.90(d,J=2.4Hz,1H), 5.14(s,2H), 2.60(s,3H).

[0486] Step B: To a mixture of 2-acetyl-5-(benzyloxy)phenyltrifluoromethanesulfonate (13.0 g, 34.7 mmol, 1.00 equivalent) and 1,1-bis(diphenylphosphino)ferrocene (1.93 g, 3.47 mmol, 0.10 equivalent) in DMF (100 mL) and methanol (10.0 mL), triethylamine (17.6 g, 174 mmol, 24.2 mL, 5.00 equivalent) and palladium(II) acetate (780 mg, 3.47 mmol, 0.10 equivalent) were added all at once under a nitrogen atmosphere at 20°C. The reaction mixture was heated to 80°C with stirring for 16 hours under a carbon monoxide (50 Psi) atmosphere. The mixture was then cooled to 15°C and concentrated under reduced pressure at 40°C to obtain the residue. The residue was poured into water (100 mL) and stirred for 5 minutes. The aqueous phase was extracted with ethyl acetate (50.0 mL x 3). The combined organic phase was washed with brine (50.0 mL), dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1~4 / 1) to obtain 2-acetyl-5-(benzyloxy)methylbenzoate (5.60 g, 16.9 mmol, 48.8% yield, 86% purity) as a yellow solid. LCMS[M+1]+: 285.0.

[0487] 1 H NMR(400MHz, CDCl3)δ=7.58(d,J=8.8Hz,1H), 7.44-7.35(m,5H), 7.26(d,J=2. 8Hz,1H), 7.08(dd,J=2.4,8.4Hz,1H), 5.14(s,2H), 3.91(s,3H), 2.53(s,3H).

[0488] Step C: To a solution of 2-acetyl-5-(benzyloxy)methylbenzoate (4.60 g, 16.2 mmol, 1.00 equivalent) in ethanol (50.0 mL), hydrazine hydrate (2.48 g, 48.5 mmol, 2.41 mL, 98% purity, 3.00 equivalent) was slowly added dropwise at 25°C, and the reaction mixture was stirred at 95°C for 30 minutes. The reaction mixture was cooled to 15°C, poured into ice water (w / w=1 / 1) (100 mL), and stirred for 5 minutes to obtain a suspension. The obtained suspension was filtered, the filter cake was collected, and dried under reduced pressure to obtain 7-(benzyloxy)-4-methylphthalazine-1(2H)-one (4.00 g, crude) as a yellow solid. LCMS[M+1]+: 267.0.

[0489] Step D: 7-(benzyloxy)-4-methylphthalazine-1(2H)-one (860 mg, 3.23 mmol, 1.00 equivalent) was gradually added to phosphorus oxychloride (14.2 g, 92.6 mmol, 8.60 mL, 28.7 equivalents) at 25°C, and the reaction mixture was stirred at 120°C for 3 hours. The mixture was cooled to 25°C and concentrated under reduced pressure to obtain the residue. The residue was slowly poured into ice water (50.0 mL), the pH was adjusted to 8 with saturated sodium bicarbonate aqueous solution (50.0 mL), and the mixture was stirred for 5 minutes. The aqueous phase was extracted with ethyl acetate (50.0 mL x 3). The combined organic phases were washed with brine (50.0 mL), dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 6-6-(benzyloxy)-4-chloro-1-methylphthalazine (740 mg, crude) as a white solid. LCMS[M+1]+:284.9.

[0490] Step E: To a solution of 6-(benzyloxy)-4-chloro-1-methylphthalazine (120 mg, 421 μmol, 1.00 equivalent) and tert-butyl(R)-(2-(5-(1-aminoethyl)thiophen-2-yl)benzyl)(methyl)carbamate (102 mg, 295 μmol, 0.70 equivalent) in dimethyl sulfoxide (1.00 mL), cesium fluoride (192 mg, 1.26 mmol, 46.6 μL, 3.00 equivalent) was added. The mixture was then stirred at 130 °C for 16 hours and diluted with ethyl acetate (30.0 mL). The combined organic fraction was washed with brine (3 × 8 mL), dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the residue. The residue was purified by 12 g of silica gel column flash chromatography eluted with petroleum ether / ethyl acetate = 0-100%, yielding tert-butyl(R)-(2-(5-(1-((7-(benzyloxy)-4-methylphthalazine-1-yl)amino)ethyl)thiophen-2-yl)benzyl)(methyl)carbamate (60.0 mg, 44.2 μmol, 10.5% yield, 43.8% purity) as a brown solid. LCMS[M+1]+: 595.3.

[0491] Step F: To a solution of tert-butyl(R)-(2-(5-(1-((7-(benzyloxy)-4-methylphthalazine-1-yl)amino)ethyl)thiophen-2-yl)benzyl in methanol (3.00 mL), a solution of (methyl)carbamate (60.0 mg, 100 μmol, 1.00 equivalent) was added, to which Pd / C (10.7 mg, 10.1 μmol, 10% purity, 0.10 equivalent) was added. The mixture was then stirred at 30°C for 3 hours. Next, the mixture was filtered, and the filter cake was washed with methanol (5.00 mL) and dichloromethane (10.0 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by reverse-phase HPLC (column: Phenomenex Synergi C18 150×30mm×4um; mobile phase: Phase A: [water (0.1% TFA)], Phase B: acetonitrile; B%: 42%~62%) to obtain tert-butyl(R)-(2-(5-(1-((7-hydroxy-4-methylphthalazine-1-yl)amino)ethyl)thiophen-2-yl)benzyl)(methyl)carbamate (15.0 mg, 29.7 μmol, 29.5% yield) as a white solid. LCMS[M+1]+: 505.3.

[0492] Step G: To a solution of tert-butyl(R)-(2-(5-(1-((7-hydroxy-4-methylphthalazine-1-yl)amino)ethyl)thiophen-2-yl)benzyl)(methyl)carbamate (13.0 mg, 25.8 μmol, 1.00 equivalent) and (R)-tetrahydrofuran-3-yl-4-methylbenzenesulfonate (9.16 mg, 30.9 μmol, 1.20 equivalents) in DMF (0.10 mL), cesium fluoride (15.0 mg, 98.8 μmol, 3.64 μL, 3.83 equivalents) was added. The mixture was stirred at 90°C for 2 hours, then poured into water (5.00 mL) and filtered. The filtrate was extracted with ethyl acetate (10 mL x 2), the combined organic layers were washed with brine (10.0 mL), dried on anhydrous sodium sulfate, and concentrated under vacuum to obtain the residue tert-butylmethyl(2-(5-((R)-1-((4-methyl-7-(((S)-tetrahydrofuran-3-yl)oxy)phthalazine-1-yl)amino)ethyl)thiophen-2-yl)benzyl)carbamate (14.8 mg, 25.8 μmol, 100% yield) as a yellow oil, which was used without further purification. LCMS[M+1]+: 575.3.

[0493] Step H: To a solution of tert-butylmethyl(2-(5-((R)-1-((4-methyl-7-(((S)-tetrahydrofuran-3-yl)oxy)phthalazine-1-yl)amino)ethyl)thiophen-2-yl)benzyl)carbamate (10.0 mg, 17.4 μmol, 1.00 equivalent) in dichloromethane (0.50 mL), 2,6-lutidine (18.6 mg, 173 μmol, 20.3 μL, 10.0 equivalent) was added, followed by TMSOTf (19.3 mg, 87.0 μmol, 15.7 μL, 5.00 equivalent). The mixture was stirred at 20°C for 1 hour, and then the solvent was evaporated under a nitrogen atmosphere. The crude product was purified by reverse-phase HPLC (column: Agela DuraShell C18 150×25mm×5um; mobile phase: Phase A: [water (0.05% NH3H2O ​​+ 10mM NH4HCO3)], Phase B: acetonitrile; B%: 36%~66%) to obtain 4-methyl-N-((R)-1-(5-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)-7-(((S)-tetrahydrofuran-3-yl)oxy)phthalazine-1-amine (2.20 mg, 4.64 μmol, 26.6% yield) as a white solid. LCMS[M+1]+: 475.2.

[0494] 1 H NMR(400MHz,CD3OD)δ=8.02(d,J=8.8Hz,1H), 7.70(d,J=2.4Hz,1H), 7.39-7.52(m,2H), 7.2 5-7.38(m,3H), 7.09(d,J=2.8Hz,1H), 6.92(d,J=3.2Hz,1H), 5.90(q,J=6.8Hz,1H), 5.30(br s,1H), 3.88-4.09(m,4H), 3.81(s,2H), 2.72(s,3H), 2.29-2.44(m,1H), 2.26(s,3H), 2.18(br dd,J=5.6,12.0Hz,1H), 1.81(d,J=7.2Hz,3H).

[0495] Following the instructions for teaching General Reaction Scheme VI and preparing Example 7-1, the following compounds of Formula (I) shown in Table 7, Examples 7-2 to 7-7, were prepared. [Table 7-1] [Table 7-2]

[0496] Following the instructions for teaching General Reaction Scheme IV and preparing Example 8-3 (see below), the following compounds of Formula (I) and Example 8-1 were prepared, and Example 8-2, shown in Table 8, was prepared. Example 8-1 (R)-4,7-dimethyl-N-(1-(5-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)phthalazine-1-amine [ka] [Table 8]

[0497] Example 8-3 [ka] (R)-7-Methoxy-4-methyl-N-(1-(5-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)phthalazine-1-amine [ka] Step A: To a solution of methyl 2-bromo-5-methoxybenzoate (3.00 g, 12.2 mmol, 1.00 equivalent) and tributyl(1-ethoxyvinyl) stannane (4.64 g, 12.9 mmol, 4.34 mL, 1.05 equivalent) in dioxane (30.0 mL), Pd(PPh3)2Cl2 (258 mg, 367 μmol, 0.03 equivalent) was added. The mixture was then stirred under a nitrogen atmosphere at 80°C for 18 hours. Next, the reaction mixture was poured into water (30.0 mL) and extracted with ethyl acetate (30.0 mL x 2). The organic layer was washed with brine (30.0 mL), dried on anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was used directly without further purification to obtain methyl 2-(1-ethoxyvinyl)-5-methoxybenzoate (2.80 g, 11.9 mmol, 96.8% yield, assumed 100% purity) as a brown oil. LCMS[M+1]+: 237.1.

[0498] Step B: A mixture of methyl 2-(1-ethoxyvinyl)-5-methoxybenzoate (2.50 g, 10.6 mmol, 1.00 equivalent) and 10% aqueous hydrogen chloride solution (386 mg, 10.6 mmol, 378 μL, 1.00 equivalent) in THF (20.0 mL) was stirred at 20°C for 1 hour. The reaction mixture was then poured into water (20.0 mL) and extracted with ethyl acetate (25.0 mL × 3). The organic layer was washed with brine (50.0 mL), dried on anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (0-20% ethyl acetate / petroleum ether) to obtain methyl 2-acetyl-5-methoxybenzoate (1.40 g, 5.72 mmol, 54.1% yield, 85.1% purity) as a yellow oil. LCMS[M+1]+: 209.0.

[0499] 1 H NMR (400MHz, CD3OD) δ=2.51(s,3H)3.86(d,J=10.0Hz,6H)7.06-7.15(m,2H)7.70-7.79(m,1H).

[0500] Step C: To a solution of 2-acetyl-5-methoxymethylbenzoate (1.30 g, 6.24 mmol, 1.00 equivalent) in ethanol (15.0 mL), hydrazine hydrate (938 mg, 18.7 mmol, 910 μL, 98% purity, 3.00 equivalent) was added. The mixture was then stirred at 80°C for 1 hour under a nitrogen atmosphere. Next, the reaction mixture was poured into water (20.0 mL) and extracted with ethyl acetate (30.0 mL × 2). The organic layer was washed with brine (30.0 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the residue. The crude product was used in the next step without purification to obtain 7-methoxy-4-methylphthalazine-1(2H)-one (1.10 g, 5.74 mmol, 91.9% yield, 99.3% purity) as a white solid. LCMS[M+1]+: 191.0.

[0501] Step D: A mixture of 7-methoxy-4-methylphthalazine-1(2H)-one (0.90 g, 4.73 mmol, 1.00 equivalent) and phosphorus oxychloride (15.2 g, 99.4 mmol, 9.23 mL, 21.0 equivalents) was stirred at 115°C for 18 hours. The mixture was then poured into water (25.0 mL). Saturated sodium carbonate solution was added until the pH reached 9. The mixture was extracted with ethyl acetate (2 × 25.0 mL). The combined organic phase was washed with brine (saturated, 20.0 mL), dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by preparative TLC (SiO2, dichloromethane:methyl alcohol = 10:1) column chromatography to obtain 4-chloro-6-methoxy-1-methylphthalazine (240 mg, 1.14 mmol, 24.0% yield, 98.8% purity) as a white solid. LCMS[M+1]+:209.0.

[0502] Step E: A mixture of tert-butyl(R)-(2-(5-(1-aminoethyl)thiophen-2-yl)benzyl)(methyl)carbamate (49.3 mg, 142 μmol, 0.99 equivalents), 4-chloro-6-methoxy-1-methylphthalazine (30.0 mg, 144 μmol, 1.00 equivalent), and cesium fluoride (66.0 mg, 435 μmol, 16.0 μL, 3.02 equivalents) in dimethyl sulfoxide (1.00 mL) was stirred at 130 °C for 18 hours. The mixture was then cooled to 25 °C, diluted with ethyl acetate (5.00 mL), washed with brine (3.00 × 5 mL), dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Boston Green ODS 150×30mm×5um; mobile phase: Phase A: [water (0.1% TFA)], Phase B: acetonitrile; B%: 38%~68%) to obtain tert-butyl(R)-(2-(5-(1-((7-methoxy-4-methylphthalazine-1-yl)amino)ethyl)thiophen-2-yl)benzyl)(methyl)carbamate (10.0 mg, 18.7 μmol, 13.0% yield, 96.8% purity) as a white solid. LCMS[M+1]+: 519.2.

[0503] Step F: A mixture of tert-butyl(R)-(2-(5-(1-((7-methoxy-4-methylphthalazine-1-yl)amino)ethyl)thiophen-2-yl)benzyl)(methyl)carbamate (8.00 mg, 15.4 μmol, 1.00 equivalent) and 2,6-lutidine (16.5 mg, 154 μmol, 18.0 μL, 10.0 equivalent) in dichloromethane (2.00 mL) was mixed with TMSOTf (24.0 mg, 108 μmol, 19.5 μL, 7.00 equivalent), and the mixture was stirred under a nitrogen atmosphere at 20°C for 2 hours. N,N-diisopropylethylamine (0.10 mL) was added to the mixture, and the mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Agela DuraShell C18 150×25mm×5um; mobile phase: Phase A: [water (0.05% NH3H2O ​​+ 10mM NH4HCO3)], Phase B: acetonitrile; B%: 38%~68%) to obtain (R)-7-methoxy-4-methyl-N-(1-(5-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)phthalazine-1-amine (3.00 mg, 7.10 μmol, 46.0% yield, 99.0% purity) as a white solid. LCMS[M+1]+: 419.2.

[0504] 1 H NMR(500MHz,CD3OD)δ=8.01(d,J=9.0Hz,1H), 7.73(d,J=2.5Hz,1H), 7.49(dd,J=9.0,2.5Hz,1H), 7.44(d,J=6.5Hz,1H), 7.33-7.37(m,2H), 7.26-7.3 4(m,1H), 7.10(d,J=3.0Hz,1H), 6.93(d,J=3.5Hz,1H), 5.85-5.96(m,1H), 4.02(s,3H), 3.86(s,2H), 2.73(s,3H), 2.29(s,3H), 1.82(d,J=7.0Hz,3H).

[0505] Example 9-1 (R)-4-Methoxy-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(piperazine-1-yl)phthalazine-1-amine [ka] Step A: To a solution of 6-bromo-2,3-dihydrophthalazine-1,4-dione (3.00 g, 12.4 mmol, 1.00 equivalent) in phosphorus oxychloride (40.0 mL), N,N-diisopropylethylamine (4.02 g, 31.1 mmol, 5.42 mL, 2.50 equivalent) was added dropwise at 25°C. The reaction mixture was then stirred at 120°C for 12 hours. The mixture was cooled to 25°C and concentrated under vacuum to remove most of the phosphorus oxychloride and obtain a residue. The residue was poured into ice water (100 mL), and the resulting aqueous solution was adjusted to pH=7 with saturated sodium bicarbonate solution, and then extracted with dichloromethane (50.0 mL × 2). The combined organic phases were washed with brine (30.0 mL x 2), dried on anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain 6-bromo-1,4-dichlorophthalazine (1.20 g, 4.32 mmol, crude) as a yellow solid without further purification. LCMS[M+3]+: 279.0.

[0506] Step B: To a mixture of 6-bromo-1,4-dichlorophthalazine (500 mg, 1.80 mmol, 1.00 equivalent) and (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethane-1-amine (365 mg, 1.80 mmol, 1.00 equivalent) in DMSO (10.0 mL), potassium fluoride (313 mg, 5.40 mmol, 126 μL, 3.00 equivalent) and N,N-diisopropylethylamine (465 mg, 3.60 mmol, 627 μL, 2.00 equivalent) were added under a nitrogen atmosphere. The reaction mixture was then stirred at 130 °C for 3 hours. After this, the reaction mixture was cooled to 25 °C, diluted with ethyl acetate (20.0 mL), washed with brine (5.00 mL x 2), dried on anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by preparative TLC (petroleum ether / ethyl acetate = 3 / 1) to obtain (R)-7-bromo-4-chloro-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)phthalazine-1-amine (360 mg, 769 μmol, 42.7% yield) as a white solid. LCMS[M+3]+: 446.1.

[0507] 1 H NMR(400MHz,CDCl3)δ=8.15-8.01(m,2H), 7.99-7.79(m,1H), 7.63(d,J=8.0Hz,1H), 7.56-7.50(m,1H), 7.23(s,1H), 5.91-5.77(m,1H), 5.45(br d,J=6.4Hz,1H), 2.55(s,3H), 1.65(d,J=6.8Hz,3H).

[0508] Step C: Sodium methoxide (200 mg, 3.71 mmol, 5.00 equivalents) was added under nitrogen to a mixture of (R)-7-bromo-4-chloro-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)phthalazine-1-amine (330 mg, 742 μmol, 1.00 equivalent) in methanol (5.00 mL). The reaction mixture was stirred in a microwave reactor at 110 °C for 2 hours. The reaction mixture was then cooled to 25 °C and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1~1 / 1) to obtain (R)-7-bromo-4-methoxy-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)phthalazine-1-amine (281 mg, 638 μmol, 86.0% yield) as a white solid.

[0509] Step D: To a solution of (R)-7-bromo-4-methoxy-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)phthalazine-1-amine (240 mg, 545 μmol, 4.00 equivalents) and tert-butylpiperazine-1-carboxylate (25.4 mg, 136 μmol, 1.00 equivalent) in dioxane (5.00 mL), RuPhos Pd G3 (5.70 mg, 6.81 μmol, 0.05 equivalents) and cesium carbonate (178 mg, 545 μmol, 4.00 equivalents) were added all at once under a nitrogen atmosphere at 20°C. The mixture was stirred at 110°C for 3 hours. LC-MS indicated that the reaction was complete. The suspension was filtered through a Celite pad, and the filter cake was washed with ethyl acetate (30.0 mL). The combined filtrate was concentrated to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex Synergi C18 150×30mm×4um, mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile); gradient: 49%~69%B) to obtain tert-butyl(R)-4-(1-methoxy-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)phthalazine-6-yl)piperazine-1-carboxylate (70.0 mg, 128 μmol, 94.1% yield) as a white solid. LCMS[M+1]+: 546.3.

[0510] Step E: Trifluoroacetic acid (0.20 mL) was added to a mixture of tert-butyl(R)-4-(1-methoxy-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)phthalazine-6-yl)piperazine-1-carboxylate (50.0 mg, 91.6 μmol, 1.00 equivalent) in dichloromethane (1.00 mL). The mixture was stirred at 20°C for 1 hour. LC-MS indicated that the reaction was complete. The mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex Synergi C18 100×21.2mm×4um, using TFA water and acetonitrile as eluents; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; gradient: 14%~44%B) to obtain (R)-4-methoxy-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(piperazin-1-yl)phthalazine-1-amine (35.0 mg, 78.6 μmol, 85.7% yield) as a white solid. LCMS[M+1]+: 446.2.

[0511] 1 H NMR(400MHz,CD3OD)δ=8.18(d,J=9.2Hz,1H), 8.06(d,J=2.8Hz,1H), 7.82(dd,J=2.4,9.2Hz,1H), 7.64-7.77(m,2H), 7.36- 7.46(m,1H), 5.42(q,J=6.4Hz,1H), 4.07(s,3H), 3.75-3.86(m,4H), 3.38-3.47(m,4H), 2.51(s,3H), 1.80(d,J=6.8Hz,3H).

[0512] Following the instructions for General Reaction Scheme III and the preparation of Example 9-1, the following compounds of Formula (I) shown in Table 9, Example 9-2 were prepared: [Table 9]

[0513] Example 10-1 (R)-4-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(piperidine-4-yl)phthalazine-1-amine [ka] Step A: A mixture of 7-bromo-4-methylphthalazine-1(2H)-one (4 g, 16.73 mmol, 1.00 equivalent) in POCl3 (75.54 g, 492.66 mmol, 45.78 mL, 29.44 equivalents) was stirred at 20°C under an N2 atmosphere, then heated to 100°C and stirred for 5 hours. The mixture was cooled to 20°C and concentrated under reduced pressure. The residue was slowly poured into water and neutralized with saturated NaHCO3 until pH=8. Ethyl acetate (100 mL) was then added to the mixture and stirred at 25°C for 30 minutes. The mixture was filtered and the filter cake was collected. The residue was purified using a silica gel column (0-55% petroleum ether / siRNA) to obtain 6-bromo-4-chloro-1-methylphthalazine (2.2 g, 8.54 mmol, 51.06% yield) as a yellow solid.

[0514] 1 H NMR (500MHz, DMSO-d6) δ 8.41 (d, J = 1.5 Hz, 1H), 8.29-8.34 (m, 1H), 8.24-8.28 (m, 1H), 2.89-2.93 (m, 3H).

[0515] Step B: To a mixture of 6-bromo-4-chloro-1-methylphthalazine (0.6 g, 2.32 mmol, 1.00 equivalent) and (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethane-1-amine (472 mg, 2.32 mmol, 1.00 equivalent) in DMSO (4 mL), N,N-diisopropylethylamine (602 mg, 2.33 mmol, 810 μL, 2.00 equivalent) and CsF (706 mg, 4.66 mmol, 2.00 equivalent) were added all at once at 20°C under an N2 atmosphere. The mixture was stirred at 130°C for 3 hours. After that, the reaction mixture was cooled to room temperature, water (50 mL) was added to the reaction mixture, and it was extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with saturated brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified using a preparative TLC plate eluted with 50% siRNA / peterium ether to obtain (R)-7-bromo-4-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)phthalazine-1-amine (0.6 g, 1414 μmol, 60.70% yield) as a yellow oil.

[0516] Note: To avoid moisture, the reaction had to be carried out in a glove box under an N2 atmosphere. All reagents, including the solvent (DMSO), needed to be dried.

[0517] 1 H NMR(400MHz,CDCl3)δ 7.97(s,1H), 7.87-7.93(m,1H), 7.79-7.85(m,1H), 7.66(d,J=7.6Hz,1H), 7 .54(d,J=7.6Hz,1H), 7.26-7.29(m,1H), 5.88(quint,J=6.4Hz,1H), 5.12(br s,1H), 2.78(s,3H), 2.57(s,3H), 1.66(d,J=6.8Hz,3H).

[0518] Step C: A mixture of (R)-7-bromo-4-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)phthalazine-1-amine (35.0 mg, 82.5 μmol, 1.00 equivalent) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (38.3 mg, 124 μmol, 1.50 equivalent) in tetrahydrofuran (3.00 mL) and water (0.60 mL) was to be mixed with sodium carbonate (26.2 mg, 247 μmol, 3.00 equivalent) and Pd(dppf)Cl2 (6.04 mg, 8.25 μmol, 0.10 equivalent) all at once under a nitrogen atmosphere at 20°C. The mixture was stirred at 80°C for 2 hours, then cooled to room temperature. The mixture was diluted with ethyl acetate (30.0 mL) and washed with water (10.0 mL x 3). The combined organic layer was washed with brine (20.0 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product as yellow oil. The yellow oil was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 2 / 1) to obtain tert-butyl(R)-4-(1-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)phthalazine-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (32.0 mg, 60.8 μmol, 73.7% yield) as yellow oil. LCMS[M+1]+: 527.3.

[0519] Step D: To a solution of tert-butyl(R)-4-(1-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)phthalazine-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (14.0 mg, 26.6 μmol, 1.00 equivalent) in methanol (3.00 mL), Pd / C (3.62 mg, 3.41 μmol, 10% purity, 0.13 equivalent) was added under a nitrogen atmosphere. This suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred under hydrogen (15.0 psi) at 25°C for 2 hours, then filtered through a Celite pad, and the filter cake was washed with ethyl acetate (30.0 mL). The combined filtrate was concentrated to obtain tert-butyl(R)-4-(1-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)phthalazine-6-yl)piperidine-1-carboxylate (14.0 mg, 26.5 μmol, 99.6% yield) as a yellow oil. The crude product was used directly in the next step without further purification. LCMS[M+1]+: 529.3.

[0520] Step E: A mixture of tert-butyl(R)-4-(1-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)phthalazine-6-yl)piperidine-1-carboxylate (14 mg, 26.5 μmol, 1.00 equivalent) in dichloromethane (2.00 mL) and trifluoroacetic acid (0.40 mL) was stirred at 20°C for 2 hours, then concentrated to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex Synergi C18 150×30mm×4um, using TFA water and acetonitrile as eluents; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; gradient: 20%~50% B) to obtain (R)-4-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(piperidine-4-yl)phthalazine-1-amine (9.00 mg, 21.0 μmol, 79.3% yield) as a yellow solid. LCMS[M+1]+: 429.1.

[0521] 1 H NMR(400MHz,CD3OD)δ=8.67(s,1H), 8.37(d,J=8.8Hz,1H), 8.12(d,J=8.4Hz,1H), 7.73(d, J=8.4Hz,1H), 7.55(d,J=8.0Hz,1H), 7.29(t,J=7.6Hz,1H), 5.57(q,J=6.8Hz,1H), 3.61(br d,J=12.8Hz,2H), 3.20-3.30(m,3H), 2.87(s,3H), 2.63(s,3H), 2.21-2.32(m,2H), 2.05-2.20(m,2H), 1.71(d,J=6.8Hz,3H).

[0522] Example 10-2 (R)-N-(1-(5-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)-7-morpholino-4-(trifluoromethyl)phthalazine-1-amine [ka] Step A: To a solution of dimethyl 4-bromophthalate (2.00 g, 7.32 mmol, 1.00 equivalent) in 1,2-dimethoxyethane (25.0 mL), CsF (223 mg, 1.46 mmol, 54.0 μL, 0.20 equivalent) and TMSCF3 (1.25 g, 8.79 mmol, 1.20 equivalent) were added. The mixture was stirred at 0-25°C for 1 hour. Next, the mixture was partitioned between ethyl acetate (1.00 mL) and water (15.0 mL). The organic phase was separated, washed with brine (15.0 mL x 3), dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a mixture of 6-bromo-3-methoxy-3-(trifluoromethyl)isobenzofuran-1(3H)-one and 5-bromo-3-methoxy-3-(trifluoromethyl)isobenzofuran-1(3H)-one (2.20 g, crude) as a colorless oil.

[0523] Step B: To a solution of 6-bromo-3-methoxy-3-(trifluoromethyl)isobenzofuran-1(3H)-one and 5-bromo-3-methoxy-3-(trifluoromethyl)isobenzofuran-1(3H)-one (2.20 g, 7.07 mmol, 1.00 equivalent) in THF (25.0 mL), hydrazine hydrate (708 mg, 14.6 mmol, 688 μL, 2.00 equivalent) was added. The mixture was stirred at 75°C for 18 hours, then concentrated under reduced pressure to remove the solvent. The residue was purified by flash silica gel chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 8 / 1) to obtain 7-bromo-4-(trifluoromethyl)phthalazine-1(2H)-one (680 mg, 2.32 mmol, 32.8% yield) as a white solid.

[0524] 1 H NMR (400MHz, CD3OD) δ=8.54(d,J=1.71Hz,1H), 8.15(dd,J=8.68,2.08Hz,1H), 7.91(dd,J=8.80,1.47Hz,1H).

[0525] Step C: To a solution of 7-bromo-4-(trifluoromethyl)phthalazine-1(2H)-one (200 mg, 683 μmol, 1.00 equivalent) in POCl3 (3.30 g, 21.5 mmol, 2.00 mL, 31.5 equivalents), pyridine (108 mg, 1.37 mmol, 110 μL, 2.00 equivalents) was added at 20°C. The mixture was stirred at 105°C for 1.5 hours, then concentrated under reduced pressure to obtain 6-bromo-4-chloro-1-(trifluoromethyl)phthalazine (210 mg, crude) as a white solid.

[0526] Step D: To a solution of 6-bromo-4-chloro-1-(trifluoromethyl)phthalazine (135 mg, 433 μmol, 1.50 equivalents) in DMSO (2.00 mL), N,N-diisopropylethylamine (112 mg, 866 μmol, 151 μL, 3.00 equivalents), KF (1.68 mg, 28.8 μmol, 6.76 μL, 0.10 equivalents), and tert-butyl(R)-(2-(5-(1-aminoethyl)thiophen-2-yl)benzyl)(methyl)carbamate (0.10 g, 289 μmol, 100 equivalents) were added. The mixture was stirred in a microwave at 130°C for 45 minutes. The mixture was diluted with water (2.00 mL) and extracted with ethyl acetate (2.00 mL x 3). The combined organic layers were washed with water (2.00 mL x 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 5 / 1) to obtain tert-butyl(R)-(2-(5-(1-((7-bromo-4-(trifluoromethyl)phthalazine-1-yl)amino)ethyl)thiophen-2-yl)benzyl)(methyl)carbamate (46.0 mg, 74.0 μmol, 25.6% yield) as a yellow oil.

[0527] Step E: The mixture of tert-butyl(R)-(2-(5-(1-((7-bromo-4-(trifluoromethyl)phthalazine-1-yl)amino)ethyl)thiophen-2-yl)benzyl)(methyl)carbamate (0.046 g, 74.0 μmol, 1.00 equivalent), morpholine (7.74 mg, 88.8 μmol, 7.82 μL, 1.20 equivalent), Cs2CO3 (72.3 mg, 222 μmol, 3.00 equivalent), Pd2(dba)3 (6.78 mg, 7.40 μmol, 0.100 equivalent), and RuPhos (6.91 mg, 14.8 μmol, 0.20 equivalent) in dioxane (0.10 mL) was degassed, purged three times with nitrogen, and then the mixture was stirred under a nitrogen atmosphere at 110°C for 1 hour. Next, the mixture was diluted with water (2.00 mL) and extracted with ethyl acetate (2.00 mL x 3). The combined organic layer was washed with brine (2.00 mL x 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 3:1) to obtain tert-butyl(R)-methyl(2-(5-(1-((7-morpholino-4-(trifluoromethyl)phthalazine-1-yl)amino)ethyl)thiophen-2-yl)benzyl)carbamate (43.0 mg, 68.5 μmol, 92.6% yield) as a yellow oil.

[0528] Step F: A solution of tert-butyl(R)-methyl(2-(5-(1-((7-morpholino-4-(trifluoromethyl)phthalazine-1-yl)amino)ethyl)thiophen-2-yl)benzyl)carbamate (50.0 mg, 79.7 μmol, 1.00 equivalent) in dichloromethane (1.00 mL) was mixed with trifluoroacetic acid (770 mg, 6.75 mmol, 0.50 mL, 84.8 equivalents). The mixture was stirred at 25°C for 20 minutes, then filtered and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex Synergi C18 100×21.2mm×4um; mobile phase: Phase A: [water (0.1% TFA)], Phase B: ACN; B%: 17%~47%) to obtain (R)-N-(1-(5-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)-7-morpholino-4-(trifluoromethyl)phthalazine-1-amine (17.5 mg, 33.1 μmol, 41.6% yield) as a white solid.

[0529] 1 H NMR(500MHz,DMSO-d6)δ 8.87(s,2H), 8.50(s,1H), 7.89-7.39(m,6H), 7.19(s,1H), 7.08(s,1H), 6.07-5.96 (m,1H), 4.23(s,2H), 3.80(s,4H), 3.46(s,4H), 2.56(s,3H), 1.80(d,J=6.9Hz,3H).

[0530] The following compounds of formula (I) and Examples 10-3 to 10-87, shown in Table 10, were prepared according to the procedures described in the instructions for General Reaction Scheme III and the preparation of Examples 10-1 and 10-2. [Table 10-1] [Table 10-2] [Table 10-3] [Table 10-4] Table 10-5 Table 10-6 Table 10-7 Table 10-8 Table 10-9 Table 10-10 Table 10-11 Table 10-12 Table 10-13 Table 10-14 Table 10-15 Table 10-16 Table 10-17 Table 10-18 Table 10-19 Table 10-20 Table 10-21

[0531] Example 11-1 (R)-(4-(1-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)phthalazine-6-yl)piperazine-1-yl)(oxetane-3-yl)methanone [ka] To a solution of (R)-4-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(piperazin-1-yl)phthalazine-1-amine (20.0 mg, 46.6 μmol, 1.00 equivalent) and oxetane-3-carboxylic acid (5.70 mg, 55.9 μmol, 1.20 equivalent) in DMF (0.50 mL), HATU (21.3 mg, 55.9 μmol, 1.20 equivalent) and N,N-diisopropylethylamine (18.1 mg, 140 μmol, 24.3 μL, 3.00 equivalent) was added. The mixture was stirred at 25°C for 1 hour, then purified by prep-HPLC (Waters Xbridge 150×25mm×5um; mobile phase: mobile phase A: [water (10mM NH4HCO3), mobile phase B: acetonitrile]; B%: 27%~57%) to obtain (R)-(4-(1-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)phthalazine-6-yl)piperazine-1-yl)(oxetan-3-yl)methanone (9.00 mg, 17.4 μmol, 37.4% yield, 99.4% purity) as an off-white solid. LCMS[M+1]+: 514.3.

[0532] 1H NMR(400MHz,CD3OD)δ=8.02(d,J=9.2Hz,1H), 7.73-7.63(m,3H), 7.50(d,J=7.6Hz,1H), 7.25(t,J=8.0Hz,1H), 5.63(q,J=7.2Hz,1H), 4.89(br s,4H), 4.33-4.22(m,1H), 3.89-3.78(m,2H), 3.69-3.58(m,4H), 3.55-3.47(m,2H), 2.67(s,3H), 2.61(s,3H), 1.64(d,J=6.8Hz,3H).

[0533] Following the instructions for teaching General Reaction Scheme III and preparing Example 11-1, the following compounds of formula (I) and Examples 11-2 to 11-6, shown in Table 11, were prepared. [Table 11-1] [Table 11-2]

[0534] Example 12-1 (R)-4-methyl-7-(4-(1-methyl-1H-pyrazole-4-yl)piperazine-1-yl)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[3,4-d]pyridazine-1-amine [ka] Step A: To a solution of 7-chloro-4-methylpyrido[3,4-d]pyridazine-1(2H)-one (5.00 g, 25.6 mmol, 1.00 equivalent) in POCl3 (137 g, 893 mmol, 83.0 mL, 34.9 equivalents), N,N-diisopropylethylamine (9.91 g, 76.7 mmol, 13.4 mL, 3 equivalents) was added dropwise at 25°C, and the reaction mixture was stirred at 110°C for 2 hours. After this, the mixture was cooled to 25°C, concentrated under vacuum to obtain a residue, diluted with ethyl acetate (300 mL) at 0°C, and the pH was adjusted to 7 by slowly adding saturated aqueous sodium bicarbonate solution. The combined organic phases were washed with brine (200 mL x 2), dried on anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain 1,7-dichloro-4-methylpyrido[3,4-d]pyridazine (4.10 g, 19.2 mmol, 74.9% yield) as a pink solid.

[0535] 1 H NMR (400MHz, DMSO-d6) δ = 9.65 (s, 1H), 8.22 (s, 1H), 3.02 (s, 3H).

[0536] Step B: To a solution of 1,7-dichloro-4-methylpyrido[3,4-d]pyridazine (300 mg, 1.40 mmol, 1.00 equivalent) and (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethane-1-amine (285 mg, 1.40 mmol, 1.00 equivalent) in DMSO (5.00 mL), potassium fluoride (244 mg, 4.20 mmol, 98.5 μL, 3.00 equivalent) and N,N-diisopropylethylamine (543 mg, 4.20 mmol, 732 μL, 3.00 equivalent) was added. The mixture was stirred at 130 °C for 12 hours, then cooled to room temperature, and water (20.0 mL) was added. The mixture was extracted with ethyl acetate (10.0 mL x 3), the combined organic layer was washed with brine (5.00 mL x 2), dried over sodium sulfate, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0~5 / 1) to obtain (R)-7-chloro-4-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[3,4-d]pyridazine-1-amine (320 mg, 840 μmol, 60.0% yield) as a yellow solid. LCMS[M+1]+: 381.0.

[0537] Step C: The mixture of (R)-7-chloro-4-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[3,4-d]pyridazin-1-amine (40.0 mg, 105 μmol, 1.00 equivalent), 1-(1-methyl-1H-pyrazole-4-yl)piperazine (58.9 mg, 210 μmol, 2.00 equivalent, TFA salt), cesium carbonate (171 mg, 525 μmol, 5.00 equivalent), and RuPhos Pd G3 (8.79 mg, 10.5 μmol, 0.10 equivalent) in dioxane (1.00 mL) was degassed, purged three times with nitrogen, and then stirred under a nitrogen atmosphere at 80°C for 10 hours. The reaction mixture was quenched with 15.0 mL of water added at 20°C, and then extracted with ethyl acetate (5.00 mL x 3). The combined organic layer was washed with brine (5.00 mL), dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75 × 30 mm × 3 μm; mobile phase: A phase: water (0.04% HCl), B phase: acetonitrile; gradient: B%: 30%~60%) to obtain (R)-4-methyl-7-(4-(1-methyl-1H-pyrazole-4-yl)piperazin-1-yl)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[3,4-d]pyridazin-1-amine (9.51 mg, 15.1% yield, HCl salt) as a pale yellow solid. LCMS[M+1]+:511.1.

[0538] 1 H NMR(400MHz,DMSO-d6)δ=9.00(s,1H), 7.72(d,J=7.6Hz,1H), 7.57(d,J=6.4Hz,1H), 7.52(d,J=7.6Hz,1H), 7.48(s,1H), 7.36(s,1H), 7.35-7.29(m,1 H), 7.25(s,1H), 5.63(quin,J=6.8Hz,1H), 3.88-3.83(m,4H), 3.75(s,2H) , 3.78-3.72(m,1H), 3.04-2.98(m,4H), 2.56(s,6H), 1.55(d,J=6.8Hz,3H).

[0539] Example 12-2 7-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-4-methyl-N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[3,4-d]pyridazine-1-amine [ka] To a solution of (R)-7-chloro-4-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[3,4-d]pyridazine-1-amine (50.0 mg, 131 μmol, 1.00 equivalent) and 6-oxa-3-azabicyclo[3.1.1]heptane (35.6 mg, 263 μmol, 2.00 equivalent, HCl), cesium carbonate (171 mg, 525 μmol, 4.00 equivalent), RuPhos (6.10 mg, 13.1 μmol, 0.10 equivalent), and Pd2(dba)3 (6.00 mg, 6.60 μmol, 0.05 equivalent) were added under a nitrogen atmosphere. The mixture was stirred at 110°C for 2 hours, then cooled to 25°C, filtered, and the filtrate was quenched with water (10.0 mL) and then extracted with ethyl acetate (30.0 mL). The combined organic layers were washed with brine (10.0 mL), dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100×25mm×5um; mobile phase: A phase: water (10mM NH4HCO3), B phase: acetonitrile; gradient: B%: 30%~60%) to obtain 7-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-4-methyl-N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[3,4-d]pyridazine-1-amine (8.64 mg, 18.9 μmol, 14.4% yield) as a yellow solid. LCMS[M+1]+: 444.1.

[0540] 1H NMR(400MHz,DMSO-d6)δ=9.03(s,1H), 7.74(d,J=7.6Hz,1H), 7.57(s,1H), 7.52(d,J=8.0Hz,1H), 7.31(t,J=8.0Hz,1H), 7.27(s,1H), 5.66(t,J=7.2 Hz,1H), 4.80(d,J=6.4Hz,2H), 3.91-3.90(m,2H), 3.75-3.68(m,2H), 3.2 3-3.16(m,1H), 2.57(s,6H), 1.95(d,J=9.2Hz,1H), 1.55(d,J=7.2Hz,3H).

[0541] SFC conditions: Chiralcel OD-3 3μm, 0.46cm id × 5cm L; Mobile phase: A for SFC CO2, B for MeOH (0.05% isopropylamine); Gradient: B in A from 10% to 40% in 3 minutes; Flow rate: 4.0 mL / min; Column temperature: 35℃; Wavelength: 220 nm; System back pressure: 100 Bar.

[0542] The following compounds of formula (I) shown in Table 12, Examples 12-3 to 12-134 were prepared according to the procedures described in the instructions for General Reaction Scheme III and the preparation of Examples 12-1 and 12-2. [Table 12-1] [Table 12-2] [Table 12-3] [Table 12-4] [Table 12-5] [Table 12-6] [Table 12-7] Table 12-8 Table 12-9 Table 12-10 Table 12-11 Table 12-12 Table 12-13 Table 12-14 Table 12-15 Table 12-16 Table 12-17 Table 12-18 Table 12-19 Table 12-20 Table 12-21 Table 12-22 Table 12-23 Table 12-24 [Table 12-25] [Table 12-26] [Table 12-27] [Table 12-28] [Table 12-29] [Table 12-30] [Table 12-31] [Table 12-32]

[0543] Example 13-1 4-Methyl-N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(((S)-tetrahydrofuran-3-yl)oxy)phthalazine-1-amine [ka] To a solution of (R)-7-bromo-4-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)phthalazine-1-amine (70.0 mg, 164 μmol, 1.00 equivalent) in toluene (1.00 mL), sodium hydride (13.2 mg, 329 μmol, 60.0% in mineral oil, 2.00 equivalent) was added at 0°C under a nitrogen atmosphere. Then, a mixture of (S)-tetrahydrofuran-3-ol (43.6 mg, 494 μmol, 3.00 equivalent), Pd2(dba)3 (15.1 mg, 16.5 μmol, 0.10 equivalent), and Tol-BINAP (22.4 mg, 33.0 μmol, 0.20 equivalent) was added. The reaction mixture was heated to 100°C and stirred for 1 hour under a nitrogen atmosphere. The mixture was then cooled to 25°C, slowly quenched with saturated ammonium chloride aqueous solution (30.0 mL), and extracted with ethyl acetate (20.0 mL x 3). The combined organic phase was washed with brine (30.0 mL), dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 80 × 40 mm × 3 μm; mobile phase: A phase: water containing 0.04% HCl, B phase: acetonitrile; B% gradient: 30%~52%) to obtain 4-methyl-N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(((S)-tetrahydrofuran-3-yl)oxy)phthalazine-1-amine (6.31 mg, 14.0 μmol, 8.5% yield, HCl salt) as a white solid. LCMS[M+1]+: 432.1

[0544] 1 H NMR(400MHz,DMSO-d6)δ=15.31(s,1H), 8.91(s,1H), 8.90-8.34(m,2H), 7.82-7.77(m,2H), 7.56(d,J=8.0Hz,1H), 7.35(t,J=8.0Hz,1H), 5.56(s,1H) ), 5.52-5.47(m,1H), 4.05-4.03(m,1H), 3.93-3.84(m,3H), 2.79(s,3H), 2.58(s,3H), 2.45-2.43(m,1H), 2.08-2.06(m,1H), 1.63(d,J=7.2Hz,3H).

[0545] SFC conditions: Chiralcel OD-3 3μm, 0.46cm id × 5cm L; Mobile phase: MeOH (0.05% isopropylamine); Gradient: B in A from 10% to 40% in 3 minutes; Flow rate: 4.0 mL / min; Column temperature: 35℃; Wavelength: 220 nm

[0546] Example 13-2 (R)-4-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(oxetane-3-yloxy)phthalazine-1-amine [ka] A mixture of (R)-7-bromo-4-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)phthalazine-1-amine (100 mg, 236 μmol, 1.00 equivalent), oxetane-3-ol (26.2 mg, 354 μmol, 1.50 equivalent), sodium tert-butoxide (68.0 mg, 707 μmol, 3.00 equivalent), and [2-(2-aminophenyl)phenyl]-methylsulfonyloxypalladium; di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (18.7 mg, 23.6 μmol, 0.10 equivalent) in dioxane (2.00 mL) was degassed, purged three times with nitrogen, and then stirred under a nitrogen atmosphere at 100°C for 1 hour. The mixture was filtered and concentrated under vacuum to obtain the residue. The residue was purified by preparative TLC (SiO2, dichloromethane / methanol = 20 / 1), and then by prep-HPLC (column: Phenomenex luna C18 150×25mm×10um; mobile phase: phase A: water (0.225% TFA), phase B: acetonitrile; phase B gradient: 17%~47%) to obtain (R)-4-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(oxetane-3-yloxy)phthalazine-1-amine (5.20 mg, 12.4 μmol, 5.25% yield, 99.4% purity) as an off-white solid. LCMS[M+1]+: 418.0.

[0547] 1 H NMR(400MHz,CD3OD)δ=8.19(d,J=8.8Hz,1H), 7.78-7.73(m,1H), 7.71(d,J=8.0Hz,1H), 7.61-7.56(m,1H), 7.52(d,J=7.6Hz,1H), 7.26(t,J=8.0Hz,1H), 5.69-5.59(m,2H), 5.21-5.12(m,2H), 4.81-4.75(m,2H), 2.75(s,3H), 2.63(s,3H), 1.67(d,J=7.2Hz,3H).

[0548] The following compounds of formula (I) and Example 13-3, shown in Table 13, were prepared according to the procedures described in the instructions for General Reaction Scheme III and the preparations for Examples 13-1 and 13-2. [Table 13]

[0549] Example 14-1 [ka] Step A: To a solution of 6-6-bromo-4-chloro-1-methylphthalazine (500 mg, 1.94 mmol, 1.00 equivalent) in chloroform (8.00 mL), NBS (380 mg, 2.14 mmol, 1.10 equivalent) and AIBN (48.0 mg, 0.29 mmol, 0.15 equivalent) were added, and the reaction mixture was stirred at 90°C for 3 hours. The reaction mixture was then cooled to 25°C, quenched with water (20.0 mL), and extracted with ethyl acetate (30.0 mL x 3). The combined organic layer was washed with brine (25.0 mL x 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to obtain 6-bromo-1-(bromomethyl)-4-chlorophthalazine (180 mg, 535 μmol, 27.6% yield) as a yellow solid. LCMS[M+3]+: 336.6.

[0550] 1H NMR (400MHz, DMSO-d6) δ = 8.52-8.50 (m, 1H), 8.41 (dd, J = 1.2, 3.6Hz, 2H), 5.42 (s, 1H), 5.31 (s, 1H).

[0551] Step B: To a solution of dimethylamine (48.2 mg, 1.07 mmol, 0.05 mL, 2.00 equivalents, HCl salt) in tetrahydrofuran (10.0 mL), N,N-diisopropylethylamine (207 mg, 1.61 mmol, 0.28 mL, 3.00 equivalents) was added. Then, 6-bromo-1-(bromomethyl)-4-chlorophthalazine (180 mg, 0.54 mmol, 1.00 equivalent) was added to the reaction mixture, and the mixture was stirred at 25°C for 12 hours. The mixture was diluted with water (30.0 mL) and extracted with ethyl acetate (30.0 mL x 3). The combined organic layers were washed with brine (30.0 mL x 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 1 / 1, Rf = 0.4) to obtain 1-(6-bromo-4-chlorophthalazine-1-yl)-N,N-dimethylmethaneamine (80.0 mg, 266 μmol, 49.7% yield) as a yellow solid. LCMS[M+3]+: 301.9

[0552] 1 H NMR (400MHz, DMSO-d6) δ=8.51(d,J=8.8Hz,1H), 8.44(d,J=1.6Hz,1H), 8.30(dd,J=2.0,8.8Hz,1H), 4.02(s,2H), 2.22(s,6H).

[0553] Step C: Potassium fluoride (69.6 mg, 1.20 mmol, 0.03 mL, 3.00 equivalent) was added to a solution of 1-(6-bromo-4-chlorophthalazine-1-yl)-N,N-dimethylmethaneamine (120 mg, 0.40 mmol, 1.00 equivalent) and (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethane-1-amine (89.2 mg, 0.44 mmol, 1.10 equivalent) in dimethyl sulfoxide (3.00 mL), and the reaction mixture was stirred at 130°C for 2 hours. The reaction mixture was cooled to 25°C, quenched with water (20.0 mL), and extracted with ethyl acetate (20.0 mL x 3). The combined organic layer was washed with brine (20.0 mL x 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 1 / 1, Rf = 0.2) to obtain (R)-7-bromo-4-((dimethylamino)methyl)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)phthalazine-1-amine (90.0 mg, 192 μmol, 48.2% yield) as a yellow oil. LCMS[M+1]+: 467.0.

[0554] Step D: To a solution of (R)-7-bromo-4-((dimethylamino)methyl)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)phthalazine-1-amine (60.0 mg, 0.13 mmol, 1.00 equivalent), morpholine (28.0 mg, 0.32 mmol, 0.03 mL, 2.50 equivalents), cesium carbonate (125 mg, 0.39 mmol, 3.00 equivalents), and RuPhos (12.0 mg, 0.03 mmol, 0.20 equivalents) in dioxane (8.00 mL), Pd2(dba)3 (11.8 mg, 0.02 mmol, 0.10 equivalents) was added, the mixture was degassed, purged three times with nitrogen, and the reaction mixture was stirred at 100°C for 2 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25°C, diluted with water (20.0 mL), and extracted with ethyl acetate (30.0 mL x 3). The combined organic layer was washed with brine (25.0 mL x 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 1 / 1) to obtain (R)-4-((dimethylamino)methyl)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-morpholinophthalazine-1-amine (5.75 mg, 12.1 μmol, 9.45% yield, 99.9% purity) as a yellow solid. LCMS[M+1]+: 474.3.

[0555] 1 H NMR(400MHz,DMSO-d6)δ=8.09(d,J=8.8Hz,1H), 7.76(d,J=8.0Hz,1H), 7.62(s,1H), 7.58(dd,J=2.0,8.8Hz,1H), 7.52(br d,J=7.2Hz,2H), 7.32(t,J=7.6Hz,1H), 5.77-5.67(m,1H), 3.86-3.80(m,4H), 3.45-3.40(m,4H), 3.31(br s,2H), 2.58(s,3H), 2.16(br s,6H), 1.56(d,J=7.2Hz,3H).

[0556] SFC conditions: Chiralcel OD-3 50×4.6mm ID, 3um mobile phase: Phase A for CO2, Phase B for MeOH (0.05% DEA), gradient elution: MeOH (0.05% DEA) in CO2 from 5% to 40%, flow rate: 3 mL / min, detector: PDA, column temperature: 35°C, back pressure: 100 Bar.

[0557] Example 14-2 [ka] Step A: To a mixture of 6-bromo-1-(bromomethyl)-4-chlorophthalazine (150 mg, 446 μmol, 1.00 equivalent) in dimethylformamide (15.0 mL), potassium phthalimide (116 mg, 624 μmol, 1.40 equivalent) was added under a nitrogen atmosphere at 25°C. The mixture was stirred at 85°C for 2 hours and then cooled to 25°C. Next, the mixture was diluted with water (50.0 mL) and extracted with ethyl acetate (50.0 mL x 3). The combined organic phase was washed with brine (100 mL), dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1) to obtain 2-((6-bromo-4-chlorophthalazine-1-yl)methyl)isoindoline-1,3-dione (150 mg, 373 μmol, 83.6% yield) as a yellow solid. LCMS[M+1]+: 404.0.

[0558] 1 H NMR (400MHz, DMSO-d6) δ = 8.55 (m, 2H), 8.40 (m, 1H), 7.95 (m, 2H), 7.90 (m, 2H), 5.60 (s, 2H).

[0559] Step B: To a solution of 2-((6-bromo-4-chlorophthalazine-1-yl)methyl)isoindoline-1,3-dione (130 mg, 323 μmol, 1.00 equivalent) and (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethane-1-amine (65.6 mg, 323 μmol, 1.00 equivalent) in dimethyl sulfoxide (7.00 mL), N,N-diisopropylethylamine (125 mg, 969 μmol, 169 μL, 3.00 equivalent) and potassium fluoride (56.3 mg, 969 μmol, 22.7 μL, 3.00 equivalent) were added, and the mixture was stirred in a sealed tube at 130°C for 12 hours. The reaction mixture was cooled to 25°C, diluted with water (50.0 mL), and extracted with ethyl acetate (50.0 mL x 3). The combined organic phases were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1) to obtain (R)-2-((6-bromo-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)phthalazine-1-yl)methyl)isoindoline-1,3-dione (130 mg, 228 μmol, 70.7% yield) as a yellow solid. LCMS[M+1]+: 472.2.

[0560] 1 H NMR(400MHz,DMSO-d6)δ=8.91(s,1H), 8.20-8.07(m,2H), 7.97-7.80(m,5H), 7.74(d,J=8.0Hz,1H), 7.51(d ,J=8.0Hz,1H), 7.31(t,J=8.0Hz,1H), 5.72-5.60(m,1H), 5.25(s,2H), 2.44(s,3H), 1.50(d,J=7.2Hz,3H).

[0561] Step C: To a solution of (R)-2-((6-bromo-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)phthalazine-1-yl)methyl)isoindoline-1,3-dione (100 mg, 176 μmol, 1.00 equivalent) and morpholine (61.2 mg, 703 μmol, 61.8 μL, 4.00 equivalent) in methylbenzene (10.0 mL), BINAP (21.9 mg, 35.1 μmol, 0.20 equivalent), cesium carbonate (172 mg, 527 μmol, 3.00 equivalent), and Pd2(dba)3 (16.1 mg, 17.6 μmol, 0.10 equivalent) were added at 25°C under a nitrogen atmosphere. The mixture was stirred at 100°C for 1 hour. After the reaction was complete, it was cooled to 25°C. The reaction mixture was quenched with water (50.0 mL) and extracted with ethyl acetate (50.0 mL x 3). The combined organic phase was washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1) to obtain (R)-2-((4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-morpholinophthalazine-1-yl)methyl)isoindoline-1,3-dione (65.0 mg, 113 μmol, 64.3% yield) as a yellow solid. LCMS[M+1]+: 576.3.

[0562] 1 H NMR(400MHz,DMSO-d6)δ=8.03(br d,J=10.0Hz,1H), 7.94-7.85(m,4H), 7.74(br d,J=7.2Hz,1H), 7.65(br s,2H), 7.51(br d,J=8.0Hz,1H), 7.43(br d,J=7.2Hz,1H), 7.31(br t,J=6.8Hz,1H), 5.72-5.67(m,1H), 5.18(s,2H), 3.83(m,4H), 3.45(m,4H), 2.44(s,3H), 1.51(d,J=7.2Hz,3H).

[0563] Step D: To a solution of (R)-2-((4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-morpholinophthalazine-1-yl)methyl)isoindoline-1,3-dione (60.0 mg, 104 μmol, 1.00 equivalent) in ethanol (6.00 mL), hydrazine hydrate (47.0 mg, 938 μmol, 45.6 μL, 9.00 equivalent) was added under a nitrogen atmosphere at 25°C. The mixture was stirred at 25°C for 1 hour, then quenched with water (10.0 mL), and extracted with ethyl acetate (10.0 mL x 3). The combined organic layer was washed with brine (30.0 mL), dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by reverse-phase HPLC (water (0.04% HCl) / CH3CN) to obtain (R)-4-(aminomethyl)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-morpholinophthalazine-1-amine (5.81 mg, 13.0 μmol, 12.5% ​​yield, hydrochloride) as a yellow solid. LCMS[M+1]+: 446.1.

[0564] 1 H NMR(400MHz,DMSO-d6)δ=8.62(br s,3H), 8.12(br s,2H), 7.79(br d,J=7.6Hz,2H), 7.61(br d,J=8.0Hz,1H), 7.38(br t,J=8.0Hz,1H), 5.66(br d,J=6.4Hz,1H), 4.56(br s,2H), 3.81(br t,J=4.8Hz,4H), 3.62(br s,4H), 2.53(m,3H), 1.70(br d,J=5.6Hz,3H).

[0565] Example 14-3 3-((R)-1-((7-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-4-((methylamino)methyl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile [ka] Step A: To a solution of (R)-3-(1-((7-chloro-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile (30.0 mg, 88.8 μmol, 1.00 equivalent) in dioxane (1.00 mL), selenium dioxide (19.7 mg, 178 μmol, 19.3 μL, 2.00 equivalent) was added, and the mixture was stirred at 100 °C for 1 hour. Next, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1~5 / 1) to obtain (R)-3-(1-((7-chloro-4-formylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile (16.0 mg, 45.5 μmol, 51.2% yield) as a yellow solid.

[0566] 1 H NMR(400MHz,DMSO-d6)δ=10.06(s,1H), 9.99(s,1H), 9.09(br d,J=6.8Hz,1H), 8.76(s,1H), 7.78(br d,J=8.0Hz,1H), 7.66(br d,J=7.6Hz,1H), 7.36(br t,J=8.0Hz,1H), 5.81(br d,J=6.4Hz,1H), 2.69(s,3H), 1.63(br d,J=6.8Hz,3H).

[0567] Step B: To a solution of (R)-3-(1-((7-chloro-4-formylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile (106 mg, 301 μmol, 1.00 equivalent) and methylamine tetrahydrofuran solution (2.0 M, 360 μL, 2.39 equivalents) in THF (3.00 mL), acetic acid (1.81 mg, 30.1 μmol, 1.72 μL, 0.10 equivalent) was added, and the mixture was stirred at 50°C for 30 minutes. After this, sodium triacetoxyborohydride (192 mg, 904 μmol, 3.00 equivalent) was added, and immediately thereafter the mixture was poured into water (5.00 mL). The aqueous phase was extracted with ethyl acetate (10.0 mL x 3), the combined organic phase was washed with brine (10.0 mL x 2), dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (R)-3-(1-((7-chloro-4-((methylamino)methyl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile (65.0 mg, 177 μmol, 58.8% yield) as a yellow solid. LCMS[M+1]+: 367.2.

[0568] Step C: To a solution of (R)-3-(1-((7-chloro-4-((methylamino)methyl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile (34.0 mg, 92.7 μmol, 1.00 equivalent) and (Boc)2O (22.3 mg, 102 μmol, 23.4 μL, 1.10 equivalent) in DCM (0.50 mL), DMAP (1.13 mg, 9.27 μmol, 0.10 equivalent) was added, and the mixture was stirred at 25°C for 1 hour. Next, the mixture was concentrated under reduced pressure, and the residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 2 / 1) to obtain (R)-((7-chloro-1-((1-(3-cyano-2-methylphenyl)ethyl)amino)pyrido[3,4-d]pyridazin-4-yl)methyl)(methyl)carbamate (35.0 mg, 75.0 μmol, 80.9% yield) as a yellow solid.

[0569] 1H NMR(400MHz,CD3OD)δ=9.43(br s,1H), 8.50(s,1H), 7.72(d,J=7.2Hz,1H), 7.52(dd,J=1.2,7.6Hz,1H), 7.29-7.24(m,1H), 5 .68-5.62(m,1H), 2.78-2.75(m,5H), 1.63(d,J=7.2Hz,3H), 1.49-1.41(m,9H), 1.22(s,3H).

[0570] Step D: Add cesium fluoride (19.5 mg, 128 μmol, 4.74 μL, 2.00 equivalents) and N,N-diisopropylethylamine (16.6 mg, 128 μmol, 22.4 μL, 2.00 equivalents) to a solution of tert-butyl(R)-((7-chloro-1-((1-(3-cyano-2-methylphenyl)ethyl)amino)pyrido[3,4-d]pyridazin-4-yl)methyl)(methyl)carbamate (30.0 mg, 64.3 μmol, 1.00 equivalents) and ((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane (7.01 mg, 51.7 μmol, 0.8 equivalents, HCl) in DMSO (0.10 mL). The mixture was stirred at 130°C for 1 hour. Next, the solution was cooled to 25°C, poured into water (10.0 mL), and the aqueous phase was extracted with ethyl acetate (10.0 mL x 3). The combined organic phase was washed with brine (10.0 mL x 3), dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain tert-butyl((7-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-1-(((R)-1-(3-cyano-2-methylphenyl)ethyl)amino)pyrido[3,4-d]pyridazin-4-yl)methyl)(methyl)carbamate (30.0 mg, crude) as a yellow solid. LCMS[M+1]+: 530.2.

[0571] Step E: To a solution of tert-butyl((7-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-1-(((R)-1-(3-cyano-2-methylphenyl)ethyl)amino)pyrido[3,4-d]pyridazin-4-yl)methyl)(methyl)carbamate (18.0 mg, 34.0 μmol, 1.00 equivalent) in acetonitrile (1.50 mL), hydrochloric acid / dioxane (0.50 mL) was added, and the mixture was stirred at 0°C for 30 minutes. Next, the mixture was poured into water (5.00 mL), and the aqueous phase was extracted with ethyl acetate (5.00 mL x 3). The combined organic phase was washed with brine (5.00 mL x 3), dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC [column: 3_Phenomenex Luna C18 75×30mm×3um; mobile phase: phase A: water (0.05% HCl), phase B: acetonitrile; B%: 7%~27%] to obtain 3-((R)-1-((7-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-4-((methylamino)methyl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile (7.00 mg, 14.9 μmol, 43.8% yield, 99.1% purity, hydrochloride) as a yellow solid. LCMS[M+1]+: 430.3.

[0572] 1 H NMR(400MHz,CD3OD)δ=9.09(s,1H), 7.83(br d,J=7.6Hz,1H), 7.71(d,J=7.6Hz,1H), 7.63-7.40(m,2H), 5.56(q,J=6.4Hz,1H), 5.41(br s,1H), 4.83(s,3H), 3.96(d,J=6.8Hz,1H), 3.84(br s,1H), 3.69(br d,J=9.6Hz,1H), 3.49(br d,J=3.2Hz,1H), 2.93(s,3H), 2.64(s,3H), 2.09(br s,2H), 1.84(d,J=6.8Hz,3H).

[0573] Example 14-4 3-((R)-1-((7-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-4-((dimethylamino)methyl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile [ka] To a solution of 3-((R)-1-((7-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-4-((methylamino)methyl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile (12.0 mg, 27.9 μmol, 1.00 equivalent) and paraformaldehyde (1.68 mg) in methanol (1.00 mL), acetic acid (168 ug, 2.79 μmol, 0.16 μL, 0.10 equivalent) and sodium borohydride cyanohydride (3.51 mg, 55.9 μmol, 2.00 equivalent) were added, and the mixture was stirred at 25°C for 1 hour. Next, the mixture was poured into water (5.00 mL), and the aqueous phase was extracted with ethyl acetate (5.00 mL x 3). The combined organic phases were washed with brine (5.00 mL x 3), dried on anhydrous sodium, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC [column: 3_Phenomenex Luna C18 75 x 30 mm x 3 μm; mobile phase: phase A: water (0.05% HCl), phase B: acetonitrile; B%: 9%~29%] to obtain 3-((R)-1-((7-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-4-((dimethylamino)methyl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile (5.20 mg, 11.4 μmol, 40.8% yield, 97.2% purity, hydrochloride) as a yellow solid. LCMS[M+1]+: 444.3.

[0574] 1H NMR(400MHz,CD3OD)δ=9.11(s,1H), 7.83(br d,J=7.6Hz,1H), 7.71(d,J=7.6Hz,1H), 7.58-7.29(m,2H), 5.56(q,J=6.4Hz,1H), 5.42(br s,1H), 5.04-4.93(m,2H), 4.83-4.81(m,1H), 3.95(br d,J=7.6Hz,1H), 3.82(br s,1H), 3.67(br s,1H), 3.48(br s,1H), 3.11(s,6H), 2.64(s,3H), 2.08(br s,2H), 1.84(br d, J = 6.8 Hz, 3H).

[0575] Following the instructions for teaching General Reaction Scheme III and preparing Examples 14-3 to 14-4, the following compounds of formula (I) and Examples 14-5 to 14-6, shown in Table 14, were prepared. [Table 14]

[0576] Example 15-1 N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-4-methyl-7-(((S)-tetrahydrofuran-3-yl)oxy)phthalazine-1-amine [ka] Step A: To a solution of 6-bromo-4-chloro-1-methylphthalazine (605 mg, 2.35 mmol, 1.10 equivalents) in DMSO (1.50 mL), potassium fluoride (372 mg, 6.41 mmol, 150 μL, 3.00 equivalents) and (R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethane-1-amine (commercially available, 500 mg, 2.14 mmol, 1.00 equivalent) were added. The mixture was stirred at 130°C for 2 hours. The reaction mixture was quenched with added water (3.00 mL) at 20°C, diluted with ethyl acetate (5.00 mL), and extracted with ethyl acetate (5.00 mL x 3). The combined organic layer was washed with brine (5.00 mL x 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate, 1:1) to obtain (R)-7-bromo-4-methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)phthalazine-1-amine (260 mg, 571 μmol, 26.8% yield) as a yellow oil. LCMS[M+1]+: 455.0.

[0577] Step B: To a solution of (R)-7-bromo-4-methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)phthalazine-1-amine (20.0 mg, 43.9 μmol, 1.00 equivalent) in dioxane (0.50 mL) and water (0.30 mL), potassium hydroxide (4.93 mg, 87.9 μmol, 2.00 equivalent) and t-BuXPhos Pd G3 (3.49 mg, 4.39 μmol, 0.10 equivalent) were added. The mixture was stirred at 80°C for 2 hours. The mixture was diluted with water (3.00 mL) and extracted with ethyl acetate (3.00 mL x 2). The combined organic layers were washed with brine (3.00 mL x 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product (R)-1-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)phthalazine-6-ol (16.0 mg, 40.8 umol) as a brown oil, which was used in the next step without further purification. LCMS[M+1]+: 393.1.

[0578] Step C: To a solution of (R)-1-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)phthalazine-6-ol (16.0 mg, 40.8 μmol, 1.00 equivalent) in DMF (1.50 mL), cesium carbonate (39.9 mg, 122 μmol, 3.00 equivalent) and (R)-tetrahydrofuran-3-yl-4-methylbenzenesulfonate (14.8 mg, 61.2 μmol, 1.50 equivalent) were added. The mixture was stirred at 80°C for 12 hours. The residue was diluted with water (2.00 mL) and extracted with ethyl acetate (3.00 mL x 3). The combined organic layers were washed with brine (5.00 mL x 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The crude product 4-methyl-N-((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-7-(((S)-tetrahydrofuran-3-yl)oxy)phthalazine-1-amine (18.0 mg, 38.93 μmol, crude) as a brown oil is used in the next step without further purification. LCMS[M+1]+: 463.1.

[0579] Step D: To a solution of -methyl-N-((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-7-(((S)-tetrahydrofuran-3-yl)oxy)phthalazine-1-amine (18.0 mg, 38.9 μmol, 1.00 equivalent) in ethanol (1.00 mL) and water (0.20 mL), iron powder (10.9 mg, 195 μmol, 5.00 equivalent) and ammonium chloride (10.4 mg, 195 μmol, 5.00 equivalent) were added. The mixture was stirred at 80°C for 2 hours. The residue was diluted with methanol (3.00 mL), filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC [Phenomenex Gemini-NX C18 75×30mm×3um; mobile phase: phase A: water (10mM NH4HCO3), phase B: MeCN; B%: 25%~55%] to obtain N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-4-methyl-7-(((S)-tetrahydrofuran-3-yl)oxy)phthalazine-1-amine (7.00 mg, 16.2 μmol, 41.6% yield) as an off-white solid. LCMS[M+1]+: 433.2.

[0580] 1 H NMR(400MHz,CD3OD)δ=8.00(d,J=8.8Hz,1H), 7.77(d,J=2.4Hz,1H), 7.49(dd,J=2.4,9.2Hz,1H), 6.98(br d,J=2.4Hz,2H), 6.76(s,1H), 5.42(q,J=6.8Hz,1H), 5.34(br dd,J=4.4,6.0Hz,1H), 4.13-3.90(m,4H), 2.67(s,3H), 2.46-2.32(m,1H), 2.26-2.15(m,1H), 1.64(d,J=7.2Hz,3H).

[0581] Example 15-2 [ka] Step A: A solution of (R)-1-(2-methyl-5-nitro-3-(trifluoromethyl)phenyl)ethane-1-amine (250 mg, 1.01 mmol, 1.00 equivalent), 6-bromo-4-chloro-1-methylphthalazine (259 mg, 1.01 mmol, 1.00 equivalent), N,N-diisopropylethylamine (390 mg, 3.02 mmol, 526 μL, 3.00 equivalent), and potassium fluoride (175 mg, 3.02 mmol, 70.7 μL, 3.00 equivalent) in dimethyl sulfoxide (3.00 mL) was stirred in a sealed tube at 130°C for 12 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25°C, quenched with water (50.0 mL), and then extracted with ethyl acetate (30.0 mL x 3). The combined organic phases were washed with brine (20.0 mL), dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate, 0 / 1) to obtain (R)-7-bromo-4-methyl-N-(1-(2-methyl-5-nitro-3-(trifluoromethyl)phenyl)ethyl)phthalazine-1-amine (200 mg, 426 μmol, 42.3% yield) as a yellow oil. LCMS[M+1]+: 469.0.

[0582] 1 H NMR(400MHz,DMSO-d6)δ=8.81(s,1H), 8.80(s,1H), 8.25(s,1H), 8.07-8.04(m,1H), 7 .96-7.92(m,2H), 5.68-5.64(m,1H), 2.74(s,3H), 2.60(s,3H), 1.58(d,J=6.8Hz,3H).

[0583] Step B: In a solution of morpholine (44.5 mg, 511 μmol, 45.0 μL, 3.00 equivalents)(R)-7-bromo-4-methyl-N-(1-(2-methyl-5-nitro-3)-(trifluoromethyl)phenyl)ethyl)phthalazine-1-amine (80.0 mg, 170 μmol, 1.00 equivalent) and cesium carbonate (166 mg, 511 μmol, 3.00 equivalents) in dioxane (2.00 mL), RuPhos (15.9 mg, 34.1 μmol, 0.20 equivalents) and Pd2(dba)3 (15.6 mg, 17.0 μmol, 0.10 equivalents) was added under a nitrogen atmosphere. The mixture was stirred at 110°C for 1 hour, then cooled to 25°C, quenched with water (40.0 mL), and extracted with ethyl acetate (20.0 mL x 3). The combined organic phase was washed with brine (40.0 mL), dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (SiO2, dichloromethane:methanol = 10 / 1) to obtain (R)-4-methyl-N-(1-(2-methyl-5-nitro-3-(trifluoromethyl)ph...

Claims

1. Compound of formula (I), 【Chemistry 1】 or a pharmaceutically acceptable salt thereof During the ceremony, R １ is hydrogen, hydroxyl, C1-C6 alkyl, alkoxy, -N(R ６ ), -NR ２ C(O)R ６ C(O)N(R ６ ), -SO ６ alkyl, -SONR ２ alkyl, cycloalkyl, -Q-heterocyclyl, aryl, or heteroaryl, wherein the cycloalkyl, the heterocyclyl, the aryl, and the heteroaryl are each optionally substituted with one or more R ２ alkyl, -SO ２ NR ６ alkyl, cycloalkyl, -Q-heterocyclyl, aryl, or heteroaryl, wherein the cycloalkyl, the heterocyclyl, the aryl, and the heteroaryl are each optionally substituted with one or more R ２ or L-R ２ and is optionally substituted with: Each Q can independently be connected, O, or NR ６ And, X is N, Each R ２ However, independently, C1-C3 alkyl, oxo, hydroxy, halogen, cyano, hydroxyalkyl, haloalkyl, alkoxy, -C(O)N(R) ６ ) ２ , -N(R ６ ) ２ , -SO ２ Alkyl, -NR ６ C(O)C1-C3 alkyl, -C(O)cycloalkyl, -C(O)C1-C3 alkyl, -C(O)heterocyclyl, aryl, heteroaryl, or heterocyclyl, wherein each of the cycloalkyl, heterocyclyl, aryl, heteroaryl, or heterocyclyl contains one or more R １１ It is optionally replaced by R ３ However, hydrogen, C1-C6 alkyl, alkoxy, -N(R １０ ) ２ , -L-N(R １０ ) ２ , cycloalkyl, haloalkyl, or heterocyclyl, wherein the C1-C6 alkyl, the cycloalkyl, and the heterocyclyl each contain one or more R ９ It is optionally replaced by Y is a bond or heteroarylene, R ４ However, one or more R ５ These are aryl or heteroaryl compounds that are optionally substituted with each other. Each R ５ However, independently, hydroxy, halogen, cyano, hydroxyalkyl, alkoxy, C1-C3 alkyl, haloalkyl, haloalkyl-OH, -N(R) ６ ) ２ , -L-N(R ６ ) ２ , or -SO ２ It is alkyl, L is a C1-C3 alkylene, Each R ６ However, independently, they are hydrogen, C1-C3 alkyl, haloalkyl, or cycloalkyl. R ８ However, it is C1-C2 alkyl or halo-C1-C2 alkyl, Each R ９ However, they are independently hydroxy, halogen, amino, cyano, alkoxy, or C1-C3 alkyl, Each R １０ However, independently, they are hydrogen, C1-C3 alkyl, or cycloalkyl. Each R １１ However, they are independently C1-C3 alkyl, halogen, or haloalkyl, R １２ A compound or a pharmaceutically acceptable salt thereof, wherein the compound is hydrogen, a halogen, or a C1-C3 alkyl group.

2. R １ However, the heterocyclyl is an alkoxy or a -Q-heterocyclyl, and the heterocyclyl is one or more R ２ or L-R ２ The compound according to claim 1, wherein it is optionally substituted with [the specified compound].

3. R １ The compound according to claim 2, wherein is a -Q-heterocyclyl, where Q is a bond or -O-, and the heterocyclyl is morpholinyl, piperazinyl, or piperazinone.

4. R １ The compound according to claim 3, wherein the compound is a -Q-heterocyclyl, and the heterocyclyl is a cross-linked morpholinyl, a cross-linked piperazinyl, or a cross-linked piperazinone.

5. R １ The compound according to claim 2, wherein the compound is a -Q-heterocyclyl, and the heterocyclyl is a spirocyclic system containing two or more rings.

6. The compound according to claim 5, wherein the spiro ring system comprises two rings, each containing a heteroatom.

7. The compound according to claim 5, wherein the spiro ring system includes a ring that does not contain a heteroatom.

8. R １ However, it is a heteroaryl, and the heteroaryl is one or more R ２ or L-R ２ The compound according to claim 1, wherein it is optionally substituted with [the specified compound].

9. The compound according to claim 8, wherein the heteroaryl is a bicyclic or tricyclic ring system containing a non-aromatic ring.

10. The compound according to claim 9, wherein the bicyclic or tricyclic ring system is 5,6,7,8-tetrahydro-[1,2,4]triazolopyrazine, 5,6,7,8-tetrahydroimidazopyrazine, 2,4,5,6-tetrahydropyrrolopyrazolyl, 1,2,3,4-tetrahydrobenzo[4,5]imidazopyrazine, or 4,5,6,7-tetrahydropyrazolopyrazine.

11. R １ The compound according to claim 1, wherein the compound is hydrogen.

12. R １ The compound according to claim 1, wherein the compound is hydroxyl.

13. R １ However, -N(R ６ ) ２ The compound according to claim 1.

14. R １ However, -NR ６ C(O)R ６ The compound according to claim 1.

15. R １ However, -C(O)N(R ６ ) ２ The compound according to claim 1.

16. R １ However, one or more R ２ The compound according to claim 1, wherein the cycloalkyl group is optionally substituted with the compound according to claim 1.

17. The cycloalkyl group comprises one or more R ２ The compound according to claim 16, wherein the compound is cyclobutyl, cyclopentyl, or cyclohexyl, each optionally substituted with the other.

18. The cyclobutyl, cyclopentyl, or cyclohexyl is one R ２ Replaced with R ２ However, C1-C3 alkyl, alkoxy, halogen, hydroxyl, or -N(R) ６ ) ２ The compound according to claim 17.

19. R １ However, one or more R ２ The compound according to claim 1, which is an optionally substituted -Q-heterocycline.

20. The compound according to claim 19, wherein Q is a bond, and the heterocyclyl is morpholinyl, piperidinyl, piperazinyl, N-methylpiperazinyl, piperazine-2-one, 1-methylpiperazine-2-one, diazepanyl, 6,6-difluoro-1,4-diazepan-1-yl, or 4-methylthiomorpholine 1,1-dioxide.

21. Q is a bond, and the heterocyclyl is one or more R ２ The compound according to claim 19, wherein the pyrrolidinyl or tetrahydropyranil is optionally substituted in each case.

22. The pyrrolidinil or the tetrahydropyranil contains one R ２ Replaced with R ２ However, C1-C3 alkyl, alkoxy, hydroxyl, or -N(R ６ ) ２ The compound according to claim 21.

23. Q is a bond, and the heterocyclyl is one or more R ２ The compound according to claim 20, wherein piperazinyl is optionally substituted with [the specified compound].

24. The piperazinyl has one R ２ Replaced with R ２ However, the heteroaryl, -C(O)cycloalkyl, or -C(O)heterocyclyl is a heteroaryl, -C(O)cycloalkyl, or -C(O)heterocyclyl, and each of the heteroaryl, -C(O)cycloalkyl, or -C(O)heterocyclyl has one or more R １１ The compound according to claim 23, which is optionally substituted with [the specified compound].

25. R ２ However, it is a -C(O) cycloalkyl group, and the cycloalkyl group has one R １１ It is a cyclopropyl substituted with R １１ The compound according to claim 24, wherein it is a C1-C3 alkyl group.

26. R ２ However, it is a -C(O) cycloalkyl group, and the cycloalkyl group has one R １１ It is a cyclopropyl substituted with R １１ The compound according to claim 24, wherein it is a haloalkyl.

27. R ２ The compound according to claim 24, wherein the compound is a -C(O) heterocyclyl, and the heterocyclyl is oxetanil, tetrahydrofuranil, or tetrahydropyranil.

28. The compound according to claim 19, wherein Q is a bond and the heterocyclyl is a bicyclic heterocyclyl.

29. The compound according to claim 28, wherein the bicyclic heterosilyl is diazabicyclo[3.2.0]heptan-2-yl, (1R,5R)-2,6-diazabicyclo[3.2.0]heptan-2-yl, diazabicyclo[3.2.0]heptan-6-yl, (1R,5R)-2,6-diazabicyclo[3.2.0]heptan-6-yl, 6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-yl, 5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-yl, 1,3-dimethyl-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-yl, or (R)-2-methylhexahydropyrrolo[1,2-a]pyrazine-6(2H)-one.

30. The compound according to claim 19, wherein Q is O, and the heterocyclyl is azetidinil, tetrahydrofuranil, pyrrolidinil, or piperidinil.

31. R １ However, one or more R ２ The compound according to claim 1, wherein the aryl is optionally substituted with the aryl compound.

32. The aryl is one or more R ２ The compound according to claim 31, wherein the phenyl is optionally substituted with the phenyl compound.

33. where the phenyl is substituted by one R ２ and R ２ is C1-C3 alkyl, alkoxy, hydroxyl, or -N(R ６ ), ２ a compound according to claim 32.

34. R １ However, one or more R ２ The compound according to claim 1, wherein the heteroaryl is optionally substituted with .

35. The heteroaryl contains one or more R ２ The compound according to claim 34, wherein pyrazolyl is optionally substituted with the compound according to claim 34.

36. where the pyrazolyl is substituted by one R ２ and R ２ is C1-C3 alkyl, alkoxy, hydroxyl, or -N(R ６ ), ２ The compound according to claim 35.

37. R １ The compound according to claim 1, wherein it is an alkoxy.

38. The compound according to claim 37, wherein the alkoxy is methoxy.

39. The compound according to any one of claims 1 to 38, wherein Y is a heteroarylene.

40. The compound according to claim 39, wherein the heteroarylene is thiophenylene.

41. The compound according to any one of claims 1 to 40, wherein Y is a bond.

42. R ４ However, one or more R ５ The compound according to any one of claims 39 to 41, wherein each is an aryl or heteroaryl that is optionally substituted.

43. R ４ However, one or more R ５ The compound according to claim 42, wherein the aryl is optionally substituted with the aryl compound.

44. The aryl is one or more R ５ The compound according to claim 43, wherein the phenyl is optionally substituted with the phenyl compound.

45. The aforementioned phenyl has one R ５ Replaced with R ５ However, C1-C4 alkyl, haloalkyl, or -L-N(R ６ ) ２ The compound according to claim 44.

46. R ５ However, -L-N(R ６ ) ２ And L is methylene, and R is ６ However, it is hydrogen, and the other R ６ The compound according to claim 45, wherein it is a C1-C3 alkyl group.

47. The second R ６ The compound according to claim 46, wherein the compound is methyl.

48. R ５ However, -L-N(R ６ ) ２ And L is methylene, and each R ６ The compound according to claim 47, wherein it is a C1-C3 alkyl group.

49. The compound according to claim 48, wherein each C1-C3 alkyl group is methyl.

50. The aforementioned phenyl has two R ５ It is replaced by and one of the R ５ However, it is a C1-C3 alkyl group, and the other R ５ The compound according to claim 44, wherein the compound is a haloalkyl group.

51. The compound according to claim 50, wherein the C1-C3 alkyl group is methyl and the haloalkyl group is trifluoromethyl.

52. The aforementioned phenyl has two R ５ It is replaced by one R ５ However, it is a C1-C3 alkyl group, and the other R ５ However, -L-N(R ６ ) ２ The compound according to claim 44.

53. C1-C3 alkyl is methyl, L is methylene, and each R ６ The compound according to claim 46, wherein it is a C1-C3 alkyl group.

54. R ３ The compound according to any one of claims 1 to 53, wherein it is a C1-C6 alkyl group.

55. The compound according to claim 54, wherein the C1-C6 alkyl group is methyl, ethyl, or isopropyl.

56. R ３ The compound according to any one of claims 1 to 53, wherein it is a haloalkyl compound.

57. R ３ The compound according to any one of claims 1 to 53, wherein the compound is a cycloalkyl group optionally substituted with a halogenated amino, hydroxyl, or alkoxy group.

58. The compound according to claim 57, wherein the cycloalkyl is cyclopropyl.

59. R ３ The compound according to any one of claims 1 to 53, wherein the compound is an alkoxy.

60. R ３ However, -N(R １０ ) ２ The compound according to any one of claims 1 to 53.

61. R ３ The compound according to any one of claims 1 to 53, wherein the compound is hydrogen.

62. R ８ The compound according to any one of claims 1 to 61, wherein it is a C1-C2 alkyl group.

63. The compound according to claim 62, wherein the C1-C2 alkyl group is methyl.

64. R ８ The compound according to any one of claims 1 to 63, wherein it is a halo C1-C2 alkyl group.

65. The compound according to claim 64, wherein the halo C1-C2 alkyl is fluoromethyl, difluoromethyl, or trifluoromethyl.

66. The aforementioned compound, 【Chemistry 2-1】 【Chemistry 2-2】 [Chemistry 2-3] [Chemistry 2-4] 【Chemistry 2-5】 【Chemistry 2-6】 【Chemistry 2-7】 【Chemistry 2-8】 【Chemistry 2-9】 【Chemistry 2-10】 【Chemistry 2-11】 【Chemistry 2-12】 【Chemistry 2-13】 【Chemistry 2-14】 【Chemistry 2-15】 【Chemistry 2-16】 【Chemistry 2-17】 【Chemistry 2-18】 A compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof.

67. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to any one of claims 1 to 66 or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

68. A pharmaceutical composition for treating cancer, comprising a therapeutically effective amount of a compound of formula (I) described in any one of claims 1 to 66 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable salt or solvate thereof, alone or in combination with a pharmaceutically acceptable carrier, excipient, or diluent.

69. The pharmaceutical composition according to claim 68, wherein the therapeutically effective amount of the compound is 0.01 to 300 mg / kg per day.

70. The pharmaceutical composition according to claim 69, wherein the therapeutically effective amount of the compound is 0.1 to 100 mg / kg per day.

71. The aforementioned cancers include: heart: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma; Lung: Bronchogenic carcinoma (squamous cell carcinoma, anaplastic small cell carcinoma, anaplastic large cell carcinoma, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal tract: Esophagus (squamous cell carcinoma, adenocarcinoma, leiomyoma, lymphoma), stomach (carcinoma, lymphoma, leiomyoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, VIP-producing tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, chorioadenoma, hamartoma, leiomyoma); urogenital tract: kidney (glandular Cancer (Wilms tumor, lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testes (seminoma, teratoma, fetal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); liver: hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; biliary tract: gallbladder cancer, ampulla cancer, cholangiocarcinoma; Bone: Osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondrial exostosis), benign chordoma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor; Nervous system: Skull (osteoma, hemangioma, granuloma, xanthomas, osteoosteitis), Meningioma (meningioma, meningiosarcoma, glioma), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal glandoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal neurofibroma, meningioma, glioma, sarcoma); gynecology: uterus (endometrial cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified cancer), granulosa theca cell tumor, cell A pharmaceutical composition according to any one of claims 68 to 70, selected from the group consisting of: Tori-Leydig cell tumor, undifferentiated germ cell tumor, malignant teratoma; vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma); vagina (clear cell carcinoma, squamous cell carcinoma, staphyloid sarcoma (embryonic rhabdomyosarcoma), fallopian tube (carcinoma); hematology: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorder, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin lymphoma (malignant lymphoma); skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevus mole, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal gland: neuroblastoma.

72. The pharmaceutical composition according to any one of claims 68 to 71, wherein the cancer is a Ras family-related cancer.

73. The pharmaceutical composition according to claim 72, wherein the Ras family-related cancer is KRas, HRas or NRas G12C-related cancer, KRas, HRas or NRas G12D-related cancer, KRas, HRas or NRas G12S-related cancer, KRas, HRas or NRas G12A-related cancer, KRas, HRas or NRas G13D-related cancer, KRas, HRas or NRas G13C-related cancer, KRas, HRas or NRas Q61X-related cancer, KRas, HRas or NRas A146T-related cancer, KRas, HRas or NRas A146V-related cancer, or KRas, HRas or NRas A146P-related cancer.

74. The pharmaceutical composition according to claim 73, wherein the Ras family-related cancer is KRas G12C-related cancer.

75. The pharmaceutical composition according to claim 74, wherein the Ras family-related cancer is non-small cell lung cancer or pancreatic cancer.

76. The pharmaceutical composition according to any one of claims 68 to 74, wherein the cancer is an SOS1-related cancer.

77. The pharmaceutical composition according to claim 76, wherein the SOS1-related cancer is SOS1 N233S-related cancer or SOS1 N233Y-related cancer.

78. The pharmaceutical composition according to claim 76 or 77, wherein the SOS1-related cancer is lung adenocarcinoma, embryonal rhabdomyosarcoma, Sertoli cell testicular tumor, or granular cell tumor of the skin.

79. The pharmaceutical composition according to any one of claims 69 to 71, wherein the cancer is an NF-1 / NF-2 related cancer.

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